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Aging brain

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The aging brain denotes the multifaceted array of structural, functional, and molecular transformations in the central nervous system that manifest with chronological advancement, encompassing neuronal attrition, synaptic pruning, diminished white matter integrity, and heightened susceptibility to proteotoxic aggregates, though exhibiting marked heterogeneity across individuals.^[1] These alterations arise from intrinsic biological processes, including mitochondrial inefficiency and telomere attrition, rather than extrinsic insults alone, leading to a gradual erosion of neural reserve without invariably precipitating overt pathology.^[2] Key structural hallmarks include volumetric shrinkage in prefrontal cortex, hippocampus, and corpus callosum, correlating with cortical thinning and ventricular expansion, as quantified via neuroimaging modalities like MRI.^[3] Functionally, processing speed decelerates and fluid intelligence wanes, while semantic knowledge accrues, reflecting compensatory neural recruitment in preserved networks.^[4] Biochemically, oxidative stress—stemming from reactive oxygen species outpacing antioxidant defenses—exacerbates lipid peroxidation and DNA damage, intertwined with microglial-driven inflammation that propagates low-grade neuroimmune activation.^[5]^[6] Causal realism underscores that these dynamics stem from evolutionary trade-offs in somatic maintenance, wherein accumulated somatic mutations and metabolic byproducts erode proteostasis, yet lifestyle modulators like caloric restriction or exercise mitigate trajectories via enhanced autophagy and neurogenesis in select niches.^[7] Controversies persist regarding the demarcation of "successful" versus "unsuccessful" aging, with evidence challenging uniform decline narratives by highlighting superagers who defy typical atrophy through genetic and vascular resilience factors.^[8] Empirical longitudinal cohorts reveal that while amyloid-beta deposition accelerates in vulnerable cohorts, it does not universally dictate cognitive fate in non-demented senescence.^[9]

Structural and Cellular Changes

Cortical thinning and brain volume reduction

Cortical thinning, the progressive reduction in the thickness of the cerebral cortex, occurs ubiquitously during normal aging, as documented in longitudinal MRI studies of cognitively healthy individuals. Thickness declines at rates of 0.005 to 0.01 mm per year across most cortical regions, with higher rates exceeding 0.07 mm per decade observed in areas such as the primary motor cortex.^[10]^[11] Regional variations show faster thinning in prefrontal, parietal, and medial frontal cortices, at rates up to 0.14 mm per decade in parietal areas, while visual regions exhibit slower changes around 0.10 mm per decade.^[12] These patterns persist across age groups, with accelerated thinning after age 60 in high-expansion cortical zones.^[13] Accompanying cortical thinning is a broader reduction in total brain volume, averaging 2.4% per decade after age 60, affecting both gray and white matter.^[14] By the seventh decade, healthy individuals experience an average volume loss of approximately 30% from peak young-adult levels. This atrophy leads to compensatory enlargement of cerebrospinal fluid spaces, including the lateral ventricles, which can expand at rates up to 3% per year in advanced aging.^[16] Longitudinal data confirm these changes occur independently of overt pathology, with cross-sectional MRI validating consistent atrophy trajectories in normal cognition.^[17]^[18] Sex differences modulate these processes, with females exhibiting relatively preserved volume (1% larger in elderly cohorts) despite comparable atrophy rates, potentially linked to baseline brain size variations.^[19] Overall, these structural alterations reflect cumulative cellular and synaptic losses, though plasticity mechanisms may mitigate functional impacts in early stages.^[20]

Neuronal loss, synaptic pruning, and plasticity decline

In normal aging, overall neuronal loss in the human brain is minimal, typically not exceeding 10% across regions, with preservation of neuron numbers in many cortical areas despite observed volume reductions attributable to dendritic shrinkage or glial changes.^[21] ^[22] Studies of postmortem tissue indicate that significant neuron depletion is largely absent in neocortical structures until advanced age, challenging earlier assumptions of widespread cell death as the primary driver of age-related cognitive impairment.^[23] However, selective losses occur in vulnerable subcortical regions, such as the hippocampus, where densities in CA1 and CA3 subfields decrease with chronological age independently of Alzheimer's disease pathologies.^[24] ^[25] Synaptic alterations predominate over frank neuronal death, featuring substantial reductions in synapse density and efficacy that correlate more directly with functional decline.^[26] Aging brains exhibit weakened synaptic transmission and diminished short-term plasticity, with fewer functional connections per neuron, particularly in prefrontal and hippocampal circuits.^[27] These changes may stem from dysregulated pruning mechanisms, where microglia and complement pathways, normally active in developmental refinement, become overactive or imprecise, leading to excessive elimination of viable synapses.^[28] ^[29] Evidence from rodent models and human imaging supports that such synaptic stripping accelerates in mid-to-late adulthood, contributing to network inefficiency without proportional neuron loss.^[30] Neural plasticity declines progressively with age, manifesting as reduced capacity for synaptic strengthening, neurogenesis, and circuit reorganization essential for learning and adaptation.^[31] Hippocampal long-term potentiation (LTP), a cellular proxy for plasticity, weakens due to impaired glutamate signaling and calcium dynamics, alongside diminished adult neurogenesis in the dentate gyrus.^[32] This erosion links to broader molecular shifts, including lower expression of plasticity-related genes and accumulated oxidative damage to synaptic proteins, rendering older neurons less responsive to environmental stimuli.^[33] While plasticity persists into senescence—evident in compensatory recruitment of alternative brain regions—it operates at reduced efficiency, with thresholds for induction elevated by 20-50% in aged versus young cohorts per electrophysiological assays.^[34]^[35]

Glial activation and vascular remodeling

Microglial cells in the aging brain transition to a primed, pro-inflammatory state, characterized by upregulated expression of MHC class II molecules, CD11b, and cytokines such as IL-1β and TNF-α, even in the absence of acute injury.^[36] This activation is associated with morphological changes, including process retraction and dystrophic features, contributing to chronic low-grade neuroinflammation that correlates with synaptic dysfunction biomarkers in cerebrospinal fluid from individuals aged 20 to 90 years.^[37] Astrocytes similarly exhibit reactive hypertrophy, accumulation of lipofuscin and debris, and a shift toward an A1-like phenotype marked by elevated complement component C3 and reduced phagocytic efficiency, impairing their roles in glutamate uptake and neuronal support.^[38]^[39] Transcriptomic analyses reveal region-specific glial alterations, with hypothalamic and white matter astrocytes showing pronounced aging-related gene expression changes linked to impaired synaptic plasticity.^[40] Vascular remodeling in cerebral aging manifests as increased arterial tortuosity in the isocortex, basement membrane thickening, and pericyte loss, reducing capillary density by up to 20-30% in rodent models and human postmortem tissue.^[41] Endothelial cells undergo senescence, with shortened telomeres and elevated p16INK4a expression, leading to diminished nitric oxide bioavailability and impaired vasodilation.^[42] These changes culminate in blood-brain barrier (BBB) dysfunction, evidenced by increased CSF/plasma albumin ratios in healthy elderly humans (indicating leakage) and early hippocampal permeability elevations detectable via dynamic contrast-enhanced MRI as early as age 40-50.^[43]^[44] Glial activation and vascular remodeling interact causally, with microglial-derived cytokines promoting endothelial apoptosis and pericyte detachment, while astrocyte endfeet swelling disrupts tight junction integrity via matrix metalloproteinase upregulation.^[45] In mouse models, aged microglia exacerbate BBB leakage under stress, amplifying neurotoxic protein influx and oxidative damage.^[46] Human cohort studies link these combined changes to accelerated cognitive decline, independent of amyloid or tau pathology, with vascular senescent cells correlating to 15-25% greater BBB permeability in non-demented octogenarians.^[47]^[48]

Protein aggregation and proteostasis failure

Proteostasis refers to the cellular processes that ensure proper protein synthesis, folding, trafficking, and degradation to maintain protein homeostasis. In the aging brain, proteostasis failure manifests as a progressive decline in these mechanisms, resulting in the accumulation of misfolded and aggregated proteins. This disruption is a hallmark of brain aging, independent of overt neurodegenerative disease, with evidence from proteomic analyses showing widespread non-disease-associated protein aggregation in aged mammalian brains.^[49] The ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway serve as the primary degradative routes, but their efficiency diminishes with chronological age, exacerbating aggregate formation.^[50] ^[51] The UPS targets ubiquitinated misfolded proteins for degradation via 26S proteasomes, but aging impairs proteasome assembly and activity, particularly in neurons, leading to reduced clearance capacity as early as middle age.^[52] Autophagy, responsible for bulk degradation of protein aggregates and damaged organelles, also declines, with studies in aged rodent brains demonstrating fewer autophagosomes and lysosomal dysfunction, contributing to intracellular accumulation of aggregates sequestered into aggresomes.^[53] Oxidative stress, prevalent in aging neurons, further compromises chaperones like HSP70 and the UPS by damaging critical components, creating a feedback loop that promotes misfolding.^[1] Protein aggregates in the aging brain include both pathological forms, such as hyperphosphorylated tau forming neurofibrillary tangles and amyloid-beta plaques, and non-pathological inclusions from everyday proteins, observed in up to 20-30% of aged human cortical neurons without dementia.^[54] This aggregation disrupts cellular functions, including mitochondrial integrity and synaptic transmission, and correlates with cognitive decline metrics in longitudinal studies of non-diseased elderly cohorts.^[55] Proteomic profiling of aged brains reveals prolonged lifetimes of regulatory proteins involved in autophagy and ferroptosis, indicating adaptive but insufficient responses to proteostatic stress.^[56] Interventions enhancing UPS or autophagy, such as caloric restriction in animal models, mitigate aggregate burden and extend neuronal healthspan, underscoring the causal role of proteostasis failure.^[57]

Molecular and Genetic Mechanisms

Oxidative stress, mitochondrial dysfunction, and energy metabolism

Mitochondria in the aging brain exhibit impaired electron transport chain efficiency, leading to elevated production of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide, which overwhelm endogenous antioxidant systems like superoxide dismutase and glutathione peroxidase. This oxidative imbalance damages lipids, proteins, and DNA, particularly in energy-demanding neurons, accelerating cellular senescence and apoptosis. Studies in rodent models demonstrate that aged hippocampal mitochondria generate up to 30% more ROS than in young counterparts under physiological conditions, correlating with reduced mitochondrial membrane potential.^[58] ^[59] Mitochondrial dysfunction manifests through accumulated mutations in mitochondrial DNA (mtDNA), which lacks robust repair mechanisms and is proximally located to ROS sources; in human postmortem brain tissue from individuals over 70 years, mtDNA deletion levels can exceed those in younger brains by 5- to 10-fold, impairing complexes I and IV of the oxidative phosphorylation (OXPHOS) system. This dysfunction perpetuates a feedback loop: defective OXPHOS increases electron leakage and ROS, further damaging mtDNA and nuclear-encoded mitochondrial proteins, while also disrupting mitophagy—the selective autophagy of damaged mitochondria—resulting in their accumulation. In vitro experiments with neuronal cell lines exposed to aging-mimetic stressors confirm that partial OXPHOS inhibition elevates ROS by 20-50%, underscoring the causal primacy of mitochondrial impairment in oxidative escalation.^[60] ^[61] ^[62] Concomitant declines in cerebral energy metabolism arise from these processes, with aged brains showing reduced ATP synthesis rates—down by approximately 50% in cortical regions of aged rodents—and a compensatory shift toward less efficient glycolysis, as evidenced by positron emission tomography (PET) imaging in humans revealing 15-20% lower glucose uptake in prefrontal areas post-60 years. Impaired mitochondrial calcium handling exacerbates this, leading to bioenergetic deficits that compromise synaptic vesicle cycling and dendritic spine maintenance, key for neuronal signaling. Longitudinal cohort studies link these metabolic shifts to cognitive trajectories, where individuals with higher baseline oxidative markers exhibit steeper declines in executive function over 5-10 years. Interventions targeting mitochondrial biogenesis, such as PGC-1α activation, have restored ATP levels and mitigated ROS in aged animal models, suggesting reversibility within physiological limits.^[63] ^[64] ^[65]

DNA damage accumulation, telomere shortening, and repair deficits

DNA damage accumulates in post-mitotic neurons of the aging brain due to persistent exposure to reactive oxygen species (ROS) from mitochondrial respiration and high transcriptional activity, resulting in elevated levels of oxidative lesions such as 8-oxoguanine and single- or double-strand breaks.^[66] Unlike proliferative cells, neurons cannot mitigate damage through dilution during division, leading to a buildup that correlates with transcriptional dysregulation and synaptic dysfunction.^[66] This process accelerates in neurodegenerative conditions, where early DNA damage in vulnerable regions like the hippocampus precedes cognitive impairment by years.^[66] Telomere shortening contributes to neuronal vulnerability, occurring even in non-dividing cells through replication-independent mechanisms driven by oxidative stress and incomplete replication of terminal sequences.^[67] In murine models, post-mitotic neurons exhibit a 38.8% decline in relative telomere length by 24 months of age, independent of cell cycle phase, while proliferative neural progenitors show up to 44.7% shortening. Shortened telomeres activate DNA damage responses, inducing senescence markers like p21 and γH2AX foci, reduced neurite outgrowth, and smaller soma sizes in human iPSC-derived motor neurons with telomeres reduced to 5.6–6.1 kb.^[68] In humans, leukocyte telomere length inversely associates with hippocampal volume and predicts dementia conversion in mild cognitive impairment cases.^[69] Deficits in DNA repair pathways exacerbate damage accumulation, with age-related declines in base excision repair (BER) efficiency failing to excise oxidative adducts like 8-oxoguanine.^[70] Non-homologous end joining (NHEJ) and homologous recombination (HR) for double-strand breaks also impair, as evidenced by reduced activity of proteins like XRCC1 and ATM in aging neurons, linking repair failure to genomic instability and proteopathy in Alzheimer's and Parkinson's.^[66] Progeroid syndromes with repair mutations, such as Cockayne or Werner, demonstrate accelerated brain aging phenotypes, including neurodegeneration from unrepaired transcription-coupled damage.^[71] Overall, these interconnected processes—damage accrual, telomere attrition, and repair incompetence—drive causal neuronal dysfunction via persistent signaling of DNA damage responses, promoting inflammation and cell death without effective resolution.^[66]^[71]

Epigenetic alterations and gene expression shifts

Epigenetic modifications, including DNA methylation, histone acetylation and methylation, and non-coding RNA regulation, accumulate in the aging brain, altering chromatin structure and gene expression without changing the underlying DNA sequence. These changes contribute to a progressive dysregulation of transcriptional programs, particularly in post-mitotic neurons where epigenetic drift—stochastic divergences in methylation patterns—occurs despite limited cell division. In human cortical neurons, age-associated DNA hypermethylation at promoter regions correlates with reduced expression of genes involved in synaptic plasticity and neuronal maintenance, while global hypomethylation affects repetitive elements and intergenic regions, potentially promoting genomic instability.^[72]^[73]^[74] DNA methylation dynamics show cell-type specificity in the aging brain; neurons exhibit distinct hypermethylation patterns compared to glia, with accelerated changes in excitatory neurons linked to cognitive decline. The expression of DNA methyltransferase 1 (DNMT1), responsible for maintenance methylation, declines with age, leading to incomplete replication of methylation marks during DNA repair in non-dividing cells and resultant hypomethylation of CpG sites. Studies of postmortem human brains reveal modular methylation changes, where modules enriched for neuronal genes display progressive hypermethylation from early adulthood, correlating with downregulation of pathways for energy metabolism and vesicle transport by age 70–80. Hypermethylation at specific loci, such as those regulating neurogenic factors like BDNF, further impairs adult neurogenesis in the hippocampus.^[75]^[73]^[74] Histone modifications also shift toward repressive states in aging neurons, with decreased H3K9 acetylation and increased H3K27me3 at promoters of genes essential for learning and memory, reducing their accessibility to transcription factors. These alterations, observed in rodent models and human prefrontal cortex samples, coincide with upregulated expression of senescence-associated secretory phenotype (SASP) genes via demethylation of inflammatory loci, fostering neuroinflammation. Non-coding RNAs, including microRNAs like miR-34a, increase with age and target epigenetic regulators, amplifying gene silencing of antioxidant defenses and mitochondrial genes.^[76]^[73]^[77] Overall, these epigenetic shifts result in a coherent signature of gene expression changes: downregulation of youthful neuronal transcripts (e.g., those for synaptic proteins like PSD-95) and upregulation of stress-response and pro-apoptotic pathways, as profiled in genome-wide analyses of aging human brains. Such patterns are partially reversible in experimental rejuvenation models, where partial epigenetic reprogramming restores youthful expression profiles and improves neuronal function, suggesting causality in age-related decline. However, human data primarily derive from correlative postmortem studies, with causality inferred from conserved patterns across species and targeted interventions in cell models.^[78]^[76]^[79]

Neurotransmitter imbalances and calcium homeostasis disruption

In the aging brain, dopamine neurotransmission declines progressively, with synthesis and release decreasing by approximately 5-7% per decade in the caudate nucleus and putamen, regions critical for motor control and reward processing.^[80] This reduction correlates with diminished D2 receptor density and impaired dopamine transporter function, contributing to slower motor performance and executive dysfunction observed in older adults. Serotonin systems exhibit variable changes, including reduced 5-HT1A receptor binding in the hippocampus and raphe nuclei, which may underlie mood alterations and cognitive inflexibility, though synthesis rates remain relatively stable.^[80] Acetylcholine signaling diminishes due to selective loss of cholinergic neurons in the basal forebrain, leading to deficits in attention and memory consolidation, as evidenced by lower choline acetyltransferase activity in postmortem studies of non-demented elderly brains.^[81] Glutamatergic transmission shows increased vulnerability to excitotoxicity in aging, stemming from reduced expression of excitatory amino acid transporters like EAAT2, which impairs glutamate reuptake and prolongs synaptic exposure.^[82] This imbalance favors excessive activation of NMDA receptors, exacerbating neuronal stress. Concurrently, GABAergic inhibition weakens, with decreased GABA-A receptor subunit expression and impaired tonic inhibition, resulting in a net excitatory shift that heightens seizure susceptibility and network hyperexcitability in aged rodents and humans.^[82] These neurotransmitter perturbations collectively disrupt synaptic plasticity and circuit homeostasis, accelerating cognitive decline independent of overt neurodegeneration.^[1] Calcium homeostasis in aging neurons is profoundly disrupted, characterized by elevated basal cytosolic calcium levels and prolonged calcium transients following stimulation, attributable to upregulated L-type voltage-gated calcium channels and downregulated plasma membrane Ca2+-ATPase pumps.^[83] Mitochondrial calcium buffering capacity declines, leading to overload, reactive oxygen species production, and impaired ATP synthesis, as observed in hippocampal neurons from aged rats. Endoplasmic reticulum calcium stores deplete due to chronic inositol trisphosphate receptor hyperactivity and reduced SERCA activity, triggering unfolded protein response and apoptosis pathways.^[84] This dysregulation links to neurotransmitter imbalances, as aberrant calcium signaling amplifies glutamate release and sensitizes NMDA receptors, fostering a vicious cycle of excitotoxic damage.^[85] Human imaging studies confirm hippocampal calcium mishandling correlates with memory impairment in healthy aging, preceding amyloid pathology.^[86]

Cognitive and Functional Impacts

Memory encoding, retrieval, and consolidation deficits

Age-related deficits in memory encoding, retrieval, and consolidation contribute significantly to episodic memory decline, with empirical studies demonstrating reduced performance in tasks requiring the formation, access, and stabilization of new information.^[87] Neuroimaging evidence links these impairments to structural changes, such as hippocampal atrophy, which correlates with poorer memory outcomes in healthy older adults, independent of neuropathology.^[88] For instance, longitudinal data show that rates of hippocampal volume loss predict both baseline cognitive status and subsequent memory deterioration over time.^[89] Memory encoding in aging is characterized by diminished ability to form detailed, associative representations, particularly in the medial temporal lobe. Older adults exhibit reduced encoding-retrieval similarity in visual and temporal cortical regions, leading to shallower processing and reliance on gist-based rather than verbatim details.^[90] Functional MRI studies reveal hypoactivation in the hippocampus during encoding tasks, such as word-list learning, resulting in lower total recall rates, especially for semantically related sequences where deeper processing is required.^[87] This deficit stems from impaired synaptic plasticity and reduced neural specificity, as evidenced by weaker pattern separation in the dentate gyrus, a hippocampal subfield prone to early atrophy.^[91] Retrieval processes decline due to weakened prefrontal-hippocampal connectivity, impairing controlled search and resolution of interference. In associative memory paradigms, older individuals show an exaggerated "encoding/retrieval flip," with poorer performance when retrieval demands exceed encoding cues, reflecting diminished executive oversight from the prefrontal cortex.^[92] Neuroimaging confirms reduced activation in left prefrontal regions suited for effortful retrieval, forcing reliance on less efficient, automatic pathways and increasing susceptibility to source misattribution.^[93] Empirical tests, including free recall and recognition, quantify this as a 20-30% drop in accuracy for older cohorts compared to younger adults, exacerbated by proactive interference from prior learning.^[94] Consolidation, the offline stabilization of traces, is disrupted by age-related sleep architecture changes, including reduced slow-wave and spindle activity critical for replay-dependent strengthening. Studies using nap paradigms demonstrate intact maintenance but blunted gains in declarative memory consolidation post-sleep in older adults, particularly for high-quality encodings.^[95] Prospective memory tasks further reveal impaired sleep-dependent consolidation for time- or event-based cues, with older adults showing 15-25% less benefit from overnight intervals versus wakefulness.^[96] Hippocampal subfield atrophy, notably in CA1 and subiculum, mediates this vulnerability, as cross-network analyses indicate competition between neocortical and hippocampal signals hinders systems-level consolidation.^[97]

Executive function, attention, and processing speed declines

Executive functions, which include inhibitory control, cognitive flexibility (task switching), and working memory updating, undergo progressive decline with aging, becoming particularly evident after age 60. Longitudinal analyses reveal unique reductions in these abilities, independent of declines in more basic perceptual or memory processes, with effect sizes indicating moderate to large impairments in older adults compared to younger cohorts. Cross-sectional comparisons consistently show older individuals performing worse on tasks measuring inhibition and shifting, though updating tasks may exhibit the most pronounced deficits. These changes correlate with reduced prefrontal cortex efficiency and white matter integrity, contributing to difficulties in goal-directed behavior and decision-making. Processing speed, defined as the efficiency of neural transmission and basic cognitive operations, slows markedly from early adulthood, with longitudinal studies documenting linear declines that accelerate after age 60, representing one of the earliest and most robust markers of cognitive aging. In a 12-year follow-up, processing speed exhibited the steepest trajectory of decline among cognitive domains, outperforming even working memory in rate of loss, and predicting broader cognitive trajectories. This slowdown manifests in longer reaction times on simple perceptual-motor tasks, with meta-analytic evidence confirming age-related reductions of approximately 20-30% per decade after age 30 in healthy adults. Such changes stem from myelin degradation and reduced neural conduction velocity, amplifying deficits in complex tasks requiring rapid integration. Attention mechanisms show domain-specific declines in older adults, with selective and divided attention particularly vulnerable, as evidenced by impaired distractor suppression and slower disengagement from irrelevant cues. Feature-based attention deteriorates, leading to greater interference from task-irrelevant stimuli, while bottom-up processing efficiency wanes, exacerbating selective attention deficits under high-load conditions. However, sustained or focused attention remains relatively intact across age groups in low-distraction paradigms, challenging notions of uniform attentional decay. These selective impairments, quantified by increased error rates and prolonged response latencies in attentional control tasks, interact with executive and speed declines to heighten vulnerability to cognitive overload in multifaceted environments.^[98]^[99]^[100]^[101]

Language processing, spatial orientation, and sensory integration changes

As individuals age, language processing undergoes selective changes, with crystallized knowledge such as vocabulary often remaining stable or even improving, while fluid aspects like lexical retrieval, naming speed, and sentence production decline due to reduced processing efficiency in frontal and temporal regions.^[102] Event-related potential studies demonstrate age-related delays in lexical and syntactic processing, with older adults exhibiting prolonged N400 components indicative of semantic integration difficulties during comprehension.^[103] Production tasks reveal increased tip-of-the-tongue states and slower word retrieval, linked to white matter degradation and hippocampal atrophy, though comprehension of complex sentences is relatively spared unless compounded by hearing loss.^[104] Spatial orientation and navigation abilities deteriorate progressively, with deficits emerging as early as midlife, as evidenced by reduced path integration and reliance on egocentric route-following over allocentric strategies dependent on hippocampal function.^[105] Neuroimaging correlates include entorhinal cortex thinning and decreased functional connectivity in the medial temporal lobe, impairing the formation of cognitive maps and updating of spatial representations during movement.^[106] Older adults exhibit longer navigation times and higher error rates in virtual reality tasks, particularly in novel environments, reflecting failures in binding spatial cues with self-motion signals from the vestibular system.^[107] These changes contribute to real-world disorientation, such as getting lost in familiar settings, independent of general cognitive decline.^[108] Sensory integration, the brain's synthesis of inputs from visual, auditory, vestibular, and proprioceptive modalities, shows altered dynamics in aging, often with expanded temporal binding windows that enhance redundancy gain but impair precise temporal acuity, as measured by audiovisual speech perception tasks.^[109] Multisensory deficits, including reduced ventrospatial attention and slower cross-modal facilitation, correlate with prefrontal and parietal lobe hypometabolism, predisposing older adults to balance instability and falls through faulty postural recalibration.^[110] Cross-sectional data link dual sensory impairments to accelerated gray matter loss in sensory association cortices, with multisensory processing precision predicting executive function variance beyond unisensory declines.^[111] These alterations reflect causal disruptions in thalamocortical loops and neurotransmitter modulation, exacerbating cognitive load during everyday tasks like driving or social interaction.^[112]

Behavioral inflexibility and emotional regulation alterations

Behavioral inflexibility in the aging brain manifests as diminished capacity for set-shifting, where individuals struggle to adapt responses to changing environmental demands or switch between tasks.^[113] This deficit is evident in older adults' increased perseverative errors on tasks like the Wisconsin Card Sorting Test, reflecting impaired executive function tied to frontal lobe atrophy and white matter degradation.^[114] Neuroimaging studies link these impairments to reduced activation in the medial prefrontal cortex and dorsolateral prefrontal regions, which underpin attentional updating and rule-based flexibility.^[115] In rodent models, aged mice exhibit analogous inflexibility in reversal learning paradigms, correlating with synaptic plasticity failures in the orbitofrontal cortex.^[116] Emotional regulation alterations in aging often involve a shift toward positivity bias, with older adults prioritizing positive stimuli in attention and memory over negative ones, as demonstrated in meta-analyses of attentional and mnemonic tasks.^[117] This "positivity effect" aligns with socioemotional selectivity theory, where finite time horizons motivate emotion-focused goals, leading to enhanced recall of positive events—evident in older adults remembering 20-30% more positive than negative images relative to younger counterparts.^[118] Empirical daily-life studies confirm older adults employ acceptance strategies more frequently (up to 15% higher usage) and distraction or worry less, correlating with sustained well-being despite cognitive declines.^[119] ^[120] However, habitual suppression of emotions in some older subgroups exacerbates arousal-related memory deficits, suggesting variability influenced by baseline regulatory habits.^[121] Amygdala hypoactivation to negative stimuli underlies this bias, though prefrontal-amygdala decoupling can impair context-appropriate regulation in high-stress scenarios.^[122]

Influencing Factors

Heritable genetic variants and APOE effects

Heritability studies, primarily using twin and family designs, indicate that genetic factors account for a substantial proportion of variance in cognitive abilities and their trajectories during aging, with estimates often exceeding 50% for general cognitive function in older adults.^[123] These influences persist across domains such as memory and executive function, though heritability may decline for specific abilities like verbal skills after age 60.^[124] Genome-wide association studies (GWAS) have further elucidated the polygenic architecture, identifying dozens of loci associated with brain aging phenotypes, including accelerated brain age gap—a measure of structural and functional deviation from chronological age—and longitudinal changes in gray matter volume and white matter integrity.^[125] For example, one large-scale GWAS pinpointed 59 independent loci linked to brain age gap, implicating pathways in neurodevelopment, synaptic function, and inflammation.^[125] Another analysis revealed 25 loci influencing brain age, with overlaps to traits like cognitive performance and neurodegenerative risk.^[126] The apolipoprotein E (APOE) gene on chromosome 19 stands out as the strongest single genetic determinant of brain aging vulnerability, with its three common alleles—ε2, ε3, and ε4—exerting differential effects. The ε4 allele, present in 15-25% of populations of European descent, dose-dependently elevates late-onset Alzheimer's disease (AD) risk—approximately threefold for heterozygotes and twelvefold for homozygotes—while also accelerating non-pathological brain aging.^[127] ε4 carriers exhibit steeper cognitive decline across multiple domains, including episodic memory and executive function, even in cognitively healthy individuals, with onset of impairment advancing by 3-7 years compared to non-carriers.^[128]^[129] Neuroimaging evidence links ε4 to faster hippocampal and cortical atrophy, reduced white matter coherence, and heightened amyloid-beta deposition starting in midlife, independent of full AD diagnosis in some cohorts.^[130]^[131] These effects synergize with chronological age, amplifying multi-cognitive deterioration and AD conversion risk beyond additive expectations.^[132] Mechanistically, APOE ε4 impairs cholesterol transport, exacerbates neuroinflammation via microglial activation, and disrupts blood-brain barrier integrity, fostering oxidative stress and tau hyperphosphorylation—hallmarks of aging-related neurodegeneration.^[133] In contrast, the rarer ε2 allele confers protection, lowering AD risk by 40-50% relative to ε3 (the neutral reference allele) and associating with slower cognitive decline, preserved brain volume, and extended longevity in population studies.^[127]^[134] ε2 may enhance amyloid clearance and neuronal repair, though its benefits diminish under extreme aging or comorbid vascular burdens. Polygenic risk scores incorporating APOE alongside other loci from GWAS enhance prediction of brain aging trajectories, underscoring a multifactorial genetic basis over APOE alone.^[125] Despite these insights, environmental interactions—such as diet and vascular health—modulate APOE effects, with ε4 carriers showing amplified vulnerability to midlife obesity and metabolic dysregulation.^[135]

Lifestyle choices: diet, exercise, and sleep impacts

Adherence to diets emphasizing whole foods, such as the Mediterranean or MIND diets, has been associated in observational studies with reduced risk of cognitive decline and dementia, potentially through mechanisms like lowered inflammation and enhanced vascular function, though randomized controlled trials have yielded mixed results on slowing progression in older adults.^[136]^[137] A 2023 trial of the MIND diet in 604 older adults at risk for decline found no significant difference in cognitive scores over three years compared to a control diet, despite high adherence rates exceeding 80%.^[137] Meta-analyses of nutritional interventions indicate potential benefits for memory from nutrient-dense patterns, but causal evidence remains limited by confounding factors like socioeconomic status and baseline health.^[138] Regular physical exercise, particularly aerobic and resistance training, modestly enhances cognitive domains like executive function and processing speed in aging populations, with systematic reviews estimating risk reductions of 28% for dementia and 45% for Alzheimer's disease among active individuals.^[139] A 2024 meta-meta-analysis across age groups confirmed small but significant improvements in global cognition from exercise, independent of intensity, with effects accumulating after approximately 52 hours of total intervention.^[140] However, a 2024 systematic review reported very small associations between physical activity levels and cognitive decline trajectories, suggesting benefits may be more pronounced in preventing rather than reversing impairment.^[141] Neurobiological mechanisms include increased hippocampal volume and BDNF expression, supporting neurogenesis, though long-term adherence challenges limit population-level impacts.^[142] Optimal sleep duration of 7-8 hours per night correlates with preserved brain microstructure and lower dementia risk, while deviations—short (<6 hours) or prolonged (>9 hours)—exhibit U-shaped associations with accelerated cognitive decline and advanced brain age.^[143] Poor sleep quality, characterized by frequent awakenings or inefficiency below 85%, predicts amyloid-beta accumulation and tau pathology in cerebrospinal fluid, impairing glymphatic clearance of neurotoxic proteins during deep sleep phases.^[144] A 2025 study linked suboptimal sleep patterns to 2-3 years older brain age via MRI metrics in midlife cohorts, with improvements in duration from short to moderate ranges associated with higher global cognition scores over five years.^[145]^[146] Interventions targeting sleep hygiene may mitigate these effects, though causality requires longitudinal RCTs to disentangle from comorbidities like depression.^[147]

Demographic variations: sex differences and population genetics

Sex differences in brain aging trajectories reveal patterns of divergent neurodegeneration and cognitive impairment. Men typically exhibit faster rates of regional brain volume loss, affecting a greater number of structures including cortical and subcortical regions, as evidenced by longitudinal MRI analyses.^[148] ^[149] In contrast, women show accelerated declines in global cognition and executive function from midlife onward, though memory domains may remain relatively preserved until later stages.^[150] These patterns persist despite women's longer average lifespan, contributing to higher late-life prevalence of Alzheimer's disease (AD) among females, with incidence rates approximately twice that of males after age 85.^[151] Hormonal influences, such as estrogen decline post-menopause, and sex-specific vascular pathologies have been hypothesized as contributors, though causal mechanisms linking biological sex to these outcomes require further elucidation.00883-3) Population genetics of brain aging highlight allele frequency variations across ancestries that modulate risk for neurodegenerative conditions like AD. The APOE ε4 allele, conferring the strongest genetic susceptibility to late-onset AD (with carriers facing 3-15-fold increased risk depending on copy number), displays ethnicity-specific effects; East Asians experience amplified AD risk per ε4 copy compared to Europeans, potentially due to gene-environment interactions or linked variants.^[152] ^[153] African ancestry populations show elevated AD incidence—roughly double that of non-Hispanic whites—which correlates partly with higher frequencies of certain risk haplotypes, though socioeconomic and lifestyle confounders complicate attribution.^[154] ^[155] Genome-wide association studies (GWAS) underscore ancestry-dependent genetic architectures, yet over 80% of such research relies on European-descent cohorts, limiting insights into non-European variants that may accelerate or mitigate brain aging processes like microglial dysfunction or amyloid clearance.^[156] Emerging data from diverse cohorts reveal protective alleles enriched in long-lived populations, such as centenarians lacking AD pathology, which regulate age-related gene expression in microglia and oligodendrocytes.^[157] ^[158] These findings emphasize the need for ancestry-inclusive genomics to parse heritable versus modifiable drivers of cognitive resilience across demographics.

Socioeconomic influences versus individual agency critiques

Lower socioeconomic status (SES), encompassing factors like income, education, and occupation, correlates with accelerated brain aging, including steeper cognitive decline and elevated dementia risk. A longitudinal analysis of over 1,000 participants from the Framingham Heart Study, published in February 2025, revealed that higher lifetime SES—particularly in midlife and later adulthood—was linked to superior baseline cognitive performance, slower decline over 6-8 years, and structural brain advantages such as greater gray matter volume and reduced white matter hyperintensities on MRI.^[159] Similarly, a 2024 cohort study of 500,000 UK Biobank participants found lower SES independently predicted a 20-30% higher dementia incidence, with mechanisms implicating chronic psychosocial stress, limited healthcare access, and environmental exposures that exacerbate neuroinflammation and amyloid accumulation.00410-3/fulltext) These associations persist after adjusting for confounders like age and comorbidities, underscoring SES as a modifiable yet entrenched risk modulator via pathways like glucocorticoid dysregulation and vascular pathology.^[160] Critiques of socioeconomic determinism in brain aging research emphasize the outsized role of individual agency, arguing that structural explanations often undervalue volitional behaviors that individuals can control irrespective of baseline SES. Empirical evidence supports this: while SES disparities explain part of variance in cognitive trajectories, mediation analyses indicate unhealthy lifestyles account for only 5-10% of the SES-dementia link, implying substantial residual effects potentially addressable through personal interventions rather than systemic overhaul alone.00410-3/fulltext) For example, randomized trials like the U.S. POINTER study (2025 results) demonstrated that multidomain lifestyle modifications—combining aerobic exercise, Mediterranean diet adherence, and cognitive training—yielded 1-2 standard deviation improvements in memory and executive function among adults over 60, with benefits observed across SES strata and independent of initial deprivation.^[161] Twin and adoption studies further illustrate intra-familial divergence, where discordant lifestyle adoption (e.g., smoking cessation or physical activity) overrides shared SES environments to preserve hippocampal integrity and delay decline by up to 5 years.^[162] This tension reflects broader debates on causal attribution, where academia's frequent privileging of SES may stem from institutional biases favoring environmental over behavioral explanations, potentially inflating structural narratives at the expense of evidence for agency-driven resilience. Peer-reviewed meta-analyses affirm that volitional factors like sustained education and social engagement build cognitive reserve, buffering against SES-linked atrophy in prefrontal and temporal regions, as quantified by 10-15% variance reduction in decline rates via modifiable habits.^[163] Nonetheless, critics of pure agency models concede that low-SES constraints—such as time poverty or resource scarcity—limit choice feasibility, though data from upwardly mobile cohorts show that early agency in habit formation can decouple outcomes from origins, with high-agency individuals in disadvantaged groups exhibiting brain aging profiles akin to affluent peers.^[164] Integrating both perspectives, effective policy might target agency amplification through accessible interventions, rather than presuming determinism precludes personal efficacy.

Assessment Methods

Neuroimaging techniques: MRI, PET, and microstructural analysis

Magnetic resonance imaging (MRI) enables quantification of structural changes in the aging brain, revealing progressive gray matter atrophy, particularly in the hippocampus and prefrontal cortex, with longitudinal studies showing annual volume loss rates of approximately 0.5-1% in healthy older adults.^[17] Hippocampal subfield atrophy correlates with episodic memory decline, as evidenced by automated segmentation techniques in cohorts aged 60-80, where subiculum and CA1 regions exhibit disproportionate shrinkage linked to cognitive trajectories.^[165] Voxel-based morphometry and cortical thickness mapping further delineate region-specific thinning, with frontal and temporal lobes showing accelerated loss after age 70, independent of vascular confounders when controlling for hypertension.^[166] Positron emission tomography (PET), particularly with 18F-fluorodeoxyglucose (FDG), detects hypometabolism in aging brains, with glucose uptake reductions of 5-10% per decade in temporoparietal regions, preceding overt cognitive impairment.^[167] Amyloid PET tracers like 11C-Pittsburgh compound B quantify beta-amyloid deposition, which accumulates silently in up to 30% of cognitively normal individuals over 75, though its causal role in non-demented aging remains debated due to poor correlation with metabolism in early stages.^[168] Tau PET imaging reveals entorhinal and neocortical spread correlating with executive deficits, but longitudinal data indicate glucose hypometabolism outperforms amyloid/tau signals in predicting progression to mild cognitive impairment.^[169] Microstructural analysis via diffusion tensor imaging (DTI) assesses white matter integrity, showing age-related declines in fractional anisotropy (FA) by 0.2-0.5% annually across tracts like the corpus callosum and superior longitudinal fasciculus, reflecting demyelination and axonal loss.^[170] Mean diffusivity increases correspondingly, with steeper changes in periventricular regions linked to processing speed slowing, as FA reductions in the cingulum predict executive function variance in septuagenarians.^[171] Advanced models like neurite orientation dispersion and density imaging extend DTI by isolating dendritic density drops, revealing non-linear trajectories where integrity plateaus midlife before abrupt decline post-60, aiding differentiation of normal aging from preclinical neurodegeneration.^[172] Multimodal integration of MRI, PET, and DTI enhances predictive models, estimating "brain age" discrepancies with accuracies up to 85% for cognitive risk stratification.^[173]

Neuropsychological batteries and cognitive testing protocols

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) evaluates five cognitive domains—immediate memory, delayed memory, language, attention, and visuospatial/constructional abilities—along with a screening executive function component, yielding index scores and a total score in 20-30 minutes of administration.^[174] Developed for repeated use to monitor decline or improvement, RBANS alternate forms reduce practice effects, making it suitable for longitudinal tracking in older adults where serial assessments detect progression beyond normal age-related variability.^[175] Empirical data from dementia cohorts show RBANS total scores below 80-85 often indicate impairment, with domain-specific deficits (e.g., delayed memory below 70) correlating with neuropathological changes like hippocampal atrophy.^[176] The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery targets memory, language, praxis, and orientation through 10 core tests, including word list learning (immediate recall over three trials, averaging 15-20 words in healthy elderly), delayed recall, recognition discrimination, verbal fluency (e.g., animal naming, typically 14-18 items in 60 seconds for ages 70+), Boston Naming Test (14-15/15 correct in norms), and constructional praxis via figure copying.^[177] Total CERAD scores, summing standardized subtest performances, range from 0-100 in healthy older adults, dropping below 70 in mild impairment; validation studies confirm annualized decline rates of 4-6 points per year in Alzheimer's pathology, outperforming single tests for differential diagnosis.^[178] Norms adjust for age (e.g., 1-2 point decrement per decade post-60) and education, enhancing specificity for pathological versus normative aging.^[179] Protocols for these batteries follow standardized guidelines: pre-testing interview assesses baseline function, comorbidities, and effort; tests administered in fixed order under timed conditions by trained neuropsychologists; scoring incorporates age- and education-stratified norms (e.g., z-scores <-1.5 indicating impairment).^[180] Full evaluations span 2-6 hours, integrating batteries with targeted add-ons like Trail Making Test Part B (completion >120-150 seconds in ages 70+ signals executive slowing) or Rey Complex Figure Test delayed recall (<10-12 elements recalled flags memory decline).^[181]^[182] Computerized variants, such as digital CERAD adaptations, maintain equivalence to paper formats while enabling remote administration, though validity requires in-person validation for subtle aging effects.^[183] Batteries like RBANS and CERAD demonstrate high test-retest reliability (r=0.80-0.95 over 1-12 months) in elderly samples, with sensitivity for mild cognitive impairment around 70-85% when combined with informant reports, though false positives arise in low-education groups without demographic corrections.^[184] These protocols prioritize empirical cutoffs over subjective interpretation, relying on large normative datasets (n>1,000 per age band) to quantify deviations, such as processing speed reductions of 20-40% from young adulthood baselines in healthy aging.^[185]

Epigenetic clocks and biological age estimators

Epigenetic clocks estimate biological age by analyzing DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites across the genome, which change predictably with chronological age. Developed initially by Steve Horvath in 2013 as a multi-tissue predictor applicable to over 30 human cell types and tissues, including brain, the Horvath clock uses an elastic net regression model trained on methylation data to forecast age with high accuracy, achieving median errors of 3.6 years in blood and similar precision in postmortem brain samples.^[186] Accelerated epigenetic age, defined as the deviation where predicted age exceeds chronological age, correlates with faster brain aging trajectories, such as reduced gray matter volume and cortical thinning observed via neuroimaging.^[187] In brain tissue, epigenetic clocks reveal associations with neurodegenerative processes; for instance, accelerated Horvath clock metrics in cortical samples from individuals with Alzheimer's disease predict amyloid plaque burden and neurofibrillary tangle density, independent of chronological age.^[188] A 2025 review highlights that second-generation clocks, like GrimAge, which incorporate methylation surrogates for plasma proteins and smoking effects, better forecast brain health outcomes, including cognitive decline rates in longitudinal cohorts, with epigenetic age acceleration explaining up to 5-10% variance in episodic memory loss beyond traditional risk factors.^[189] These estimators leverage Illumina methylation arrays (e.g., 450K or EPIC) for CpG site quantification, enabling postmortem or biopsy-based assessments that outperform chronological age in predicting mortality risk stratified by brain region, such as the prefrontal cortex where acceleration exceeds 2-3 years in dementia cases.^[190] Recent advancements include brain-specific and cell-type-resolved clocks; a 2024 study developed neuron-specific epigenetic estimators from single-nucleus methylation data in human brain tissue, demonstrating that glial cell shifts account for only 12% of clock variance, while neuronal methylation drives age predictions with r > 0.95 correlation to chronological age.^[191] Long-read sequencing-based clocks, reported in 2025, refine brain aging predictions by resolving haplotype-specific methylation, improving accuracy in diverse ancestries and identifying midlife acceleration linked to APOE ε4 carriers' tau pathology risk.^[192] These tools extend to peripheral blood proxies for brain age, though tissue-specific discrepancies persist, with brain clocks showing 20-30% higher heritability (h² ≈ 0.39) than pan-tissue models.^[193] Empirical data from meta-analyses confirm epigenetic acceleration's prospective validity for brain atrophy, yet causal inference remains correlative, pending intervention trials.^[194]

Limitations of brain age models and prediction accuracy

Brain age models, which estimate chronological age from neuroimaging data such as structural MRI, often suffer from overfitting due to high-dimensional feature spaces and limited sample sizes in training datasets, leading to inflated performance on held-out data from the same cohort but poor replication across independent samples.^[195] This issue is exacerbated in machine learning approaches like support vector regression or deep neural networks, where model complexity can capture noise rather than generalizable aging signals, resulting in mean absolute errors (MAEs) that degrade from ~3 years in-sample to over 5 years in cross-cohort validations.^[196] Techniques such as cross-validation mitigate but do not eliminate this, as evidenced by systematic reviews highlighting inconsistent model comparisons due to varying evaluation criteria.^[197] Prediction accuracy is further limited by inherent biases, including age-dependent prediction errors where models underperform at the extremes of the age spectrum—overestimating young brains and underestimating old ones—due to uneven data distribution and regression-to-the-mean effects in linear models.^[198] Meta-analyses and reviews report typical MAEs of 2.5–4 years in healthy adults using T1-weighted MRI, but these drop significantly in clinical populations or when generalizing to diverse ethnicities, scanners, or acquisition protocols, with errors exceeding 5–7 years in neurodegenerative cohorts like Alzheimer's disease.^[199]^[200] The brain age gap (BAG), derived as predicted minus chronological age, correlates weakly with chronological age itself (r ≈ 0.1–0.3 beyond residuals), questioning its independence as a biomarker and revealing it as largely a proxy for prediction residuals rather than a robust measure of accelerated aging.^[201] Generalizability remains a core challenge, as models trained on predominantly White, high-socioeconomic cohorts from datasets like UK Biobank fail to predict accurately in underrepresented groups, with biases arising from population-specific genetic, environmental, or scanner variances that inflate BAG variability unrelated to pathology.^[202] Longitudinal validation is scarce, with most studies relying on cross-sectional data that conflate intra-individual aging trajectories with inter-individual differences, limiting causal inferences about progression.^[203] Multimodal integrations (e.g., combining MRI with diffusion or functional imaging) improve accuracy marginally (MAE reductions of ~0.5–1 year) but introduce new complexities like feature redundancy and increased overfitting risk without standardized protocols.^[200] Clinically, these limitations undermine BAG's utility as a standalone predictor of cognitive decline or disease risk, as it adds little explanatory power beyond chronological age for outcomes like fluid cognition, with effect sizes often <0.1 in standardized units after covariate adjustment.^[204] Reviews emphasize the need for diverse, prospective datasets and bias-corrected algorithms to enhance reliability, yet current models' sensitivity to preprocessing pipelines (e.g., FreeSurfer vs. SPM) can alter BAG by 1–2 years, eroding confidence in their deployment for personalized medicine.^[205]^[206]

Interventions and Research Frontiers

Building cognitive reserve through education and activity

Cognitive reserve refers to the brain's capacity to withstand age-related pathological changes and maintain function through preexisting neural networks and compensatory mechanisms, often accrued via enriching experiences such as formal education and mentally stimulating activities.^[207] Higher levels of education in early life are associated with an 18% reduction in dementia risk, as evidenced by a meta-analysis of 27 longitudinal studies reporting a hazard ratio (HR) of 0.82 (95% CI: 0.79–0.86).^[207] For instance, completing junior high school versus primary education correlated with an HR of 0.81 (95% CI: 0.72–0.91), suggesting that extended schooling fosters synaptic efficiency and redundancy that buffer against later cognitive decline.^[207] Engagement in cognitive activities, including reading, playing board games, and musical pursuits, similarly contributes to reserve by promoting neural plasticity. In a prospective cohort of 469 older adults followed for up to 21 years, a one-point increase in cognitive-activity score yielded an HR of 0.93 (95% CI: 0.90–0.97) for dementia, with those in the highest tertile showing a 63% lower risk (HR: 0.37, 95% CI: 0.23–0.61) compared to the lowest.^[208] Late-life cognitive stimulation further attenuates risk, with meta-analytic HRs of 0.91 (95% CI: 0.86–0.97), independent of early-life factors in some models.^[207] Lifelong accumulation amplifies these effects; in a 9-year cohort of 602 older adults, high reserve across early, adult, and late periods reduced dementia relative risk (RR) to 0.40 (95% CI: 0.20–0.81), with individual periods showing RRs of 0.57, 0.60, and 0.52, respectively.^[209] Occupational complexity in midlife and social connections in late life also proxy reserve, yielding HRs of 0.89 (95% CI: 0.78–1.01) and 0.70 (95% CI: 0.63–0.77).^[207] These associations persist across APOE ε4 genotypes, indicating broad applicability.^[209] However, while observational data support reserve-building via education and activity, causality remains unproven, as proxies like education may primarily reflect premorbid cognitive ability rather than induce protective changes.^[210] Longitudinal analyses often control for baseline cognition, yet residual confounding from socioeconomic factors or reverse causation—wherein healthier individuals sustain activities—limits inferences.^[207] Direct measures of reserve are elusive, relying on indirect indicators, and randomized trials of interventions like lifelong learning programs show modest, inconsistent gains in delaying decline.^[211] Mechanisms, such as enhanced prefrontal efficiency or dendritic arborization, are hypothesized but require neuroimaging validation beyond associations.^[207]

Pharmacological targets: senolytics, NAD+ boosters, and immune modulation

Senolytics, such as the combination of dasatinib and quercetin (D+Q), selectively eliminate senescent cells that accumulate in the aging brain, thereby reducing the senescence-associated secretory phenotype (SASP) that drives chronic inflammation and neuronal dysfunction. In aged human brain organoids, senolytic treatment diminished markers of cellular senescence, lowered inflammatory cytokine expression, and restored youthful transcriptomic signatures, indicating potential reversal of brain aging hallmarks.^[212] Preclinical studies in mouse models of Alzheimer's disease, including APP^NL-F/NL-F mice, demonstrated that intermittent D+Q administration improved spatial memory, reduced senescent glial cells, and enhanced synaptic integrity.^[213] Similarly, D+Q alleviated cognitive deficits and preserved blood-brain barrier function in models of traumatic brain injury and global cerebral ischemia, with effects persisting long-term post-treatment.^[214] ^[215] However, results vary by sex and model; one study in female APP/PS1 mice found no prevention of cognitive decline despite senescent cell clearance, highlighting potential limitations in translating efficacy across contexts.^[216] Early human pilots, such as those testing D+Q for cognitive and mobility improvements in older adults, report tolerability but await confirmatory outcomes on brain-specific endpoints.^[217] NAD⁺ boosters, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), counteract the age-related decline in NAD⁺ levels, which impairs sirtuin activity, mitochondrial bioenergetics, and DNA repair in neurons, contributing to cognitive impairment. NAD⁺ depletion accelerates with brain aging and is exacerbated in neurodegenerative conditions, disrupting neuronal survival and synaptic plasticity.^[218] In preclinical models, NR supplementation restored NAD⁺, mitigated oxidative stress and apoptosis, and rescued cognitive deficits by enhancing mitochondrial function and reducing neuroinflammation.^[219] A randomized placebo-controlled trial in older adults showed NR elevated blood NAD⁺ levels and trended toward improved brain bioenergetics via magnetic resonance spectroscopy, though cognitive benefits were not uniformly observed across participants.^[220] Systematic reviews of NAD⁺ precursors indicate neuroprotective effects in Alzheimer's models, including synaptic protection and amyloid pathology reduction, but human trials remain small-scale and primarily demonstrate safety rather than robust cognitive gains.^[221] Ongoing research emphasizes NAD⁺'s role in sirtuin-mediated longevity pathways, with boosters showing promise in delaying age-related metabolic and neuronal decline when administered mid-life.^[222] Immune modulation targets dysregulated neuroinflammation, particularly microglial activation, which shifts from protective to pro-inflammatory states in the aging brain, exacerbating neuronal loss and cognitive decline. Aging microglia exhibit reduced phagocytic efficiency and heightened SASP production, linking immune senescence to neurodegeneration.^[223] Pharmacological agents, such as TREM2 agonists or CSF1R inhibitors, aim to reprogram microglia toward homeostatic functions; for instance, TREM2 modulation enhances amyloid clearance and reduces tau pathology in Alzheimer's models.^[224] Small-molecule immunomodulators, including NLRP3 inflammasome inhibitors, suppress chronic cytokine release (e.g., IL-1β, TNF-α) and preserve synaptic integrity in aged rodent brains.^[225] Preclinical evidence supports combining immune targets with senolytics to address overlapping pathways, as senescence amplifies microglial dysfunction.^[226] Clinical pipelines include biologics like anti-TNF antibodies and novel compounds targeting JAK-STAT or complement pathways, with phase II trials reporting modest reductions in neuroinflammatory biomarkers but variable cognitive impacts.^[227] These approaches underscore causal links between unresolved inflammation and brain aging, though long-term safety and specificity remain challenges in human application.^[228]

Emerging therapies: stem cells, gene reactivation, and midlife interventions

Stem cell-based approaches, including transplantation of mesenchymal stem cells (MSCs) and utilization of their secreted factors such as exosomes, have demonstrated neuroprotective and rejuvenative effects in preclinical models of brain aging. Exosomes derived from MSCs delay brain aging by upregulating SIRT1 expression, a key regulator of cellular senescence and neuroprotection.^[229] In naturally aging rats, intravenous administration of MSCs improved cognitive function, physical performance, and extended median lifespan by 23.4% for allogeneic MSCs and 31.3% for autologous MSCs, with effects attributed to reduced inflammation and enhanced neurogenesis.^[230] A 2025 study from Cedars-Sinai generated "young" microglia-like immune cells from human induced pluripotent stem cells (iPSCs), which, when transplanted into mouse models of Alzheimer's disease, reversed cognitive decline and amyloid pathology by restoring microglial phagocytosis and reducing neuroinflammation.^[231] Human Phase 1 trials of MSC therapy have shown reduced brain inflammation and tissue loss following intracerebral injection, though long-term efficacy and safety remain under evaluation.^[232] Gene reactivation strategies, primarily through epigenetic reprogramming, target the reversal of age-associated silencing of youthful gene expression patterns in neurons. Cyclic expression of Yamanaka factors (Oct4, Sox2, Klf4, c-Myc; OSKM) has reversed age-related epigenetic alterations, such as DNA methylation drifts, in mammalian models without inducing full pluripotency or tumorigenesis.^[233] In neuronal epigenomes, partial reprogramming restores youthful chromatin states, enhancing synaptic plasticity and cognitive function while mitigating hallmarks like tau hyperphosphorylation in aging brains.^[76] Chemically induced reprogramming, using small molecules to activate endogenous Yamanaka-like pathways, has extended lifespan and improved tissue homeostasis in progeroid mice by correcting epigenetic noise, a causal driver of functional decline.^[234] These approaches show potential for neurodegenerative conditions, as OSKM-mediated rejuvenation in glial cells supports neuronal survival, though off-target risks like incomplete reprogramming necessitate precise dosing protocols.^[235] Midlife interventions represent a temporal window for averting nonlinear brain aging trajectories, with emerging metabolic therapies showing capacity to stabilize neural networks destabilizing from the mid-40s onward. Ketone supplementation, providing alternative neuronal fuel via beta-hydroxybutyrate, prevents cognitive decline when initiated around age 45 in human cohorts tracked via brain network stability metrics, bypassing midlife insulin resistance that accelerates atrophy in regions like the hippocampus.^[236] In mouse models exhibiting midlife metabolic shifts, exogenous ketones reversed epigenetic and transcriptomic markers of brain aging, restoring mitochondrial function and reducing oxidative stress without altering calorie intake.^[237] This aligns with observations of accelerated decline between ages 45-60, where interventions targeting vascular health and inflammation—such as targeted senolytics or NAD+ precursors—could intercept causal pathways like microglial senescence before late-life irreversibility.^[238] Clinical translation emphasizes early detection via epigenetic clocks, as midlife cardiovascular health optimization correlates with slower cortical thinning and preserved executive function over decades.^[239]

Key controversies: amyloid hypothesis flaws and research integrity issues

The amyloid hypothesis posits that accumulation of beta-amyloid (Aβ) peptides in the brain initiates a cascade leading to Alzheimer's disease (AD) pathology, including tau tangles, neuronal loss, and cognitive decline, a framework that has guided AD research since the 1990s.^[240] Despite its influence, empirical challenges undermine its causal primacy: amyloid plaques are present in up to 30% of cognitively normal elderly individuals without AD symptoms, indicating poor predictive specificity for dementia onset.^[241] Moreover, the extent of amyloid deposition correlates weakly or not at all with the severity or progression of cognitive impairment in AD patients, as autopsy studies show variable plaque loads across similar clinical stages.^[242] Spatial and temporal mismatches further complicate causality, with amyloid appearing years before symptoms in some cases, yet failing to align with the spread of neurodegeneration, which often follows tau pathology more closely.^[243] Anti-amyloid therapeutics have repeatedly failed to deliver meaningful clinical benefits, testing the hypothesis's validity after over two decades of investment exceeding $1 billion annually in drug development.^[244] At least 11 phase III trials of anti-amyloid antibodies or BACE inhibitors, including solanezumab, bapineuzumab, and verubecestat, terminated between 2012 and 2019 due to lack of efficacy on cognition or function, despite reducing amyloid levels.^[245] Even recent approvals like aducanumab (2021) and lecanemab (2023) show modest amyloid clearance but only marginal slowing of decline (e.g., 27% on CDR-SB scale for lecanemab), overshadowed by risks such as amyloid-related imaging abnormalities (ARIA) causing brain edema or hemorrhage in 10-20% of patients.^[246]^[247] These outcomes suggest amyloid reduction alone insufficiently addresses multifactorial aging processes like inflammation or vascular dysfunction, prompting critiques that the hypothesis overemphasizes a correlative biomarker at the expense of alternative drivers.^[248] Research integrity concerns have amplified skepticism, particularly revelations of data manipulation in foundational amyloid studies. In 2022, analysis identified duplicated and altered gel images in over 20 papers from AD labs, including a pivotal 2006 Nature study by Sylvain Lesné et al. claiming Aβ*56 oligomers specifically impair memory in rats, which amassed over 2,500 citations and bolstered amyloid-centric models.^[249] The paper was retracted in 2024 after University of Minnesota investigations confirmed image fabrication, leading to Lesné's resignation in February 2025 amid broader data integrity failures.^[250]^[251] Such incidents highlight systemic vulnerabilities in amyloid research, including publication pressures and funding biases toward plaque-targeting approaches, with NIH allocating over 70% of AD grants to amyloid-related projects despite replication shortfalls.^[252] Critics argue this "amyloid dominance" reflects institutional inertia rather than robust evidence, as peer review overlooked anomalies in high-impact journals, eroding trust in a field where preclinical hype has outpaced clinical translation.^[249] While proponents maintain the hypothesis's core via genetic links like APP mutations, these lapses underscore the need for rigorous verification to distinguish causal mechanisms from artifacts in aging brain pathology.^[253]

References

[1]
Normal Aging Induces Changes in the Brain and ...
Jun 30, 2022 · This review summarizes the structural, biochemical, metabolic, cellular, and molecular changes that occur with normal brain aging.
[2]
Crosstalk between Oxidative Stress and Aging in ... - PubMed Central
Feb 27, 2023 · Advanced aging is caused by a combination of factors: lifestyle, diet, external and internal factors, as well as oxidative stress (OS).
[3]
Structural Imaging Measures of Brain Aging - PMC - PubMed Central
The findings reveal highly consistent age-related differences in brain structure, particularly frontal lobe and medial temporal regions.Introduction · Cortical Thickness · Studies Of Evident Cerebral...
[4]
The Impact of Age on Cognition - PMC - PubMed Central
This article reviews the cognitive changes that occur with normal aging, the structural and functional correlates of these cognitive changes, ...Changes In Cognition With... · Figure 1 · Age-Related Changes In Brain...<|separator|>
[5]
Oxidative Stress and the Aging Brain: From Theory to Prevention
The key cellular event signaling ongoing inflammation in the brain is the accumulation of reactive microglia in the degenerative areas [56, 57].
[6]
a review of reactive oxygen species and prevention by antioxidants
Jan 2, 2024 · Neuroinflammation can involve the activation of mast cells, contributing to oxidative stress, in addition to other sources of reactive oxygen ...
[7]
Oxidative Stress in Cognitive and Epigenetic Aging: A Retrospective ...
In this review, we describe the evidence to show how oxidative stress is intricately linked to age-associated cognitive decline.Abstract · Introduction · Oxidative Stress and Cognitive... · Cellular and Molecular...
[8]
The first 25 years of the Northwestern University SuperAging Program
Aug 7, 2025 · ... changes considered part of average (i.e., “normal”) brain aging. This line of work is helping to revise common misperceptions about the ...1 Theoretical And Historical... · 4.2 Neurofibrillary... · 4.3 Basal Forebrain...<|separator|>
[9]
Brain aging comprises many modes of structural and functional ...
The modes represent different aspects of brain aging, showing distinct patterns of functional and structural brain change, and distinct patterns of association ...
[10]
Greater cortical thinning in normal older adults predicts later ... - NIH
The majority of these regions are getting thinner at rates between 0.005 and 0.01 mm per year.
[11]
Age-associated map of cortical thinning in mm/per decade. Absolute...
majority of the cortical mantle showed thinning rates of at least 0.01 mm/decade. The greatest rate (>0.07 mm/decade) was found in primary motor cortex. The ...
[12]
Cortical thinning in cognitively normal elderly cohort of 60 to 89 year ...
The parietal, medial frontal and medial parietal showed fastest thinning rates of 0.14, 0.12 and 0.10 mm/decade respectively while the visual region showed the ...Missing: per humans
[13]
Age-Related Changes in the Thickness of Cortical Zones in Humans
Within the age range of 60–79, thinning appears equivalent in low-expansion and high-expansion regions, whereas individuals aged 80 or older demonstrated more ...
[14]
Quantitative evaluation of brain volume among elderly individuals in ...
We noted a median rate of reduction in total brain volume of 2.4% per decade after 60 years of age. Gray and white matter both showed volume reductions with age ...
[15]
The aging human brain: A causal analysis of the effect of sex and ...
Nov 20, 2020 · We find that healthy subjects get into their seventies with an average brain volume loss of 30% from their maximum brain volume at a young age.
[16]
Characterization of Brain Volume Changes in Aging Individuals With ...
Jun 28, 2023 · The volume change rate of the lateral ventricle exhibited the largest acceleration with aging, reaching a volume loss of up to 3% per year for ...
[17]
Brain Volume Changes in Aging Individuals With Normal Cognition
Jun 28, 2023 · Although the ADNI focuses on individuals with cognitive decline and older adults, we examined ... normal brain aging and their normal variability.
[18]
Longitudinal Changes in Cortical Thickness Associated with Normal ...
Our results show widespread declines in cortical thickness during normal aging and differential rates of cortical thinning in distinct brain regions.
[19]
A Causal Analysis of the Effect of Age and Sex Differences on Brain ...
Oct 12, 2022 · We found that both age and sex were causally related to brain atrophy, with women reaching an elderly age with a 1% larger brain volume relative ...
[20]
Age-related cortical thinning in cognitively healthy individuals in ...
We provide longitudinal estimates of cortical thinning observed over 12 years in a large group (n = 396) of healthy individuals, aged 60–66 years at baseline ...
[21]
How do neurons age? A focused review on the ... - PubMed Central
Overall neuronal loss: No more than 10% overall neuronal loss in healthy physiological aging (Pannese, 2011) though there are regional differences with ...
[22]
Preservation of Neuronal Number Despite Age-Related Cortical ...
An alternative commonly cited hypothesis about brain changes with aging states that neuronal loss becomes prominent in the decades after middle age (12).
[23]
Life and death of neurons in the aging brain - PubMed - NIH
Recent quantitative studies suggest that neuron death is restricted in normal aging and unlikely to account for age-related impairment of neocortical and ...
[24]
Neuron loss associated with age but not Alzheimer's disease ...
Sep 21, 2020 · Ageing was associated with decreased CA1 and CA3 neuron densities, while AD pathologies were not correlated with changes in neuron or glia ...
[25]
Neuron loss associated with age but not Alzheimer's disease ...
Nov 9, 2020 · Ageing was associated with decreased CA1 and CA3 neuron densities, while AD pathologies were not correlated with changes in neuron or glia ...<|control11|><|separator|>
[26]
Mechanisms Underlying Brain Aging Under Normal and ...
Nov 27, 2022 · Age-related dysfunction of neural networks is not due to a loss of neurons (which is minimal in normal aging brains), but to abnormal synaptic ...
[27]
Altered Synaptic Dynamics during Normal Brain Aging
Feb 27, 2013 · The changes we describe here likely result in weaker synapses that are less capable of short-term plasticity in aged individuals, and therefore ...
[28]
Cognitive Decline in Old Age May Be Linked to Increased 'Pruning ...
A study led by BU researcher Douglas Rosene sheds new light on the potential links between age-related cognitive decline and the mechanism that helps the brain ...
[29]
Complement-mediated synapse loss in Alzheimer's disease
Complement-mediated synaptic pruning has been identified as a major contributor to synapse loss in Alzheimer's disease (AD). Multiple AD risk factors (including ...
[30]
Are Similar Processes at Work in Both Brain Development and ...
Apr 20, 2021 · These age-related changes may result in faulty synaptic pruning, albeit not enough to cause problems. Stevens theorizes that two hits to the ...
[31]
Aging and brain plasticity - PMC - NIH
Aug 1, 2018 · For a long time, it has been assumed that brain plasticity peaks at young age and then gradually decreases as one gets older.
[32]
Neural ageing and synaptic plasticity: prioritizing brain health in ...
Structural changes in the hippocampus, such as synaptic loss, one of the hallmarks of normal ageing, also play an important role in age-associated cognitive ...<|separator|>
[33]
Brain aging and rejuvenation at single-cell resolution: Neuron
Jan 8, 2025 · We review insights gleaned from single-cell omics studies of brain aging, starting with a cell-type-centric overview of age-associated changes.<|separator|>
[34]
Assessing cognitive decline in the aging brain: lessons from rodent ...
Oct 19, 2023 · Early studies suggested that aged individuals show a decrease in neuronal activation and recruit different brain regions compared to young ...
[35]
Age-related differences of motor cortex plasticity in adults
We aimed to explore age-dependent plasticity alterations in adults systematically by discerning between younger and older participants in our study.
[36]
Microglia of the Aged Brain: Primed to be Activated and Resistant to ...
Recent evidence indicates that the resident glia are key contributors to the increased inflammatory state of the CNS. Microglia. The majority of aging research ...
[37]
Glial reactivity correlates with synaptic dysfunction across aging and ...
Jul 1, 2025 · We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals.
[38]
Quantitative, structural and molecular changes in neuroglia of aging ...
The neuroglia of the central and peripheral nervous systems undergo numerous changes during normal aging. Astrocytes become hypertrophic and accumulate ...
[39]
Normal aging induces A1-like astrocyte reactivity - PNAS
Feb 7, 2018 · These findings suggest that aging induces reactivity in astrocytes, which may impact their ability to perform their normal functions in the ...
[40]
Astrocytes in aging: Neuron - Cell Press
Jan 8, 2025 · Astrocytes change their transcriptome during aging, with astrocytes in areas such as the cerebellum, the hypothalamus, and white matter-rich ...
[41]
Aging drives cerebrovascular network remodeling and functional ...
Jul 30, 2024 · Aging also causes vascular remodeling with increased arterial tortuosity in the isocortex and reduces capillary pericyte density in the ...
[42]
Mechanisms of Vascular Aging | Circulation Research
Sep 13, 2018 · In this review, the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, ...
[43]
Age‐associated changes in the blood‐brain barrier - PubMed Central
A systematic review suggests that BBB breakdown may be common in normal human ageing as evidenced by increased cerebrospinal fluid/plasma albumin ratios and ...
[44]
Blood-Brain Barrier Breakdown in the Aging Human Hippocampus
Jan 21, 2015 · Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.
[45]
The blood-brain barrier in aging and neurodegeneration - PMC
Disruption of the BBB coincides with healthy aging, but the characteristics of breakdown can become further exacerbated in neurodegenerative disorders (Table 1) ...
[46]
The blood-brain barrier in aging and neurodegeneration - Nature
Mar 31, 2022 · The alterations and breakdown of functional components of the BBB can occur naturally with aging even in the absence of underlying conditions ...
[47]
Vascular Cell Senescence Contributes to Blood–Brain Barrier ...
Our results indicate that accumulation of senescent vascular cells is associated with compromised BBB integrity, providing insights into the mechanism of BBB ...
[48]
Age-Related Decline in Blood-Brain Barrier Function is More ... - eLife
Apr 15, 2024 · There is a natural decline and breakdown of BBB function with aging as revealed by both animal and human studies (2, 3), which affects all BBB ...
[49]
Aging and the aggregating proteome - PMC
Nov 20, 2012 · There is accumulating evidence that aging leads to a collapse in protein homeostasis and widespread non-disease protein aggregation.
[50]
Ubiquitin, Proteasomes, and the Aging Brain - Science
Here we describe alterations in the aging mammalian brain that correlate with a decline in the function of the UPP and review the evidence for age-related ...<|control11|><|separator|>
[51]
Aging and diet alter the protein ubiquitylation landscape in ... - Nature
Jun 6, 2025 · Decline of UPS activity is an early event during brain aging. Ubiquitin signaling is also required for the turnover of organelles, e.g., ...
[52]
The proteasome: A key modulator of nervous system function, brain ...
Proteasome function is impaired as a consequence both of aging and neurodegenerative diseases. Many studies have demonstrated an impairment in 26S proteasome ...
[53]
Extensive accumulation of misfolded protein aggregates during ...
Jan 26, 2023 · We found intracellular age-ggregation in the aged brain, where misfolded proteins are sequestered into aggresomes. Aggresomes have been studied ...
[54]
Extensive accumulation of misfolded protein aggregates during ...
Jan 26, 2023 · Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging.
[55]
Proteostasis failure exacerbates neuronal circuit dysfunction and ...
Failed proteostasis is a well-documented feature of Alzheimer's disease, particularly, reduced protein degradation and clearance.
[56]
Protein lifetimes in aged brains reveal a proteostatic adaptation ...
May 20, 2022 · Other rLL proteins are linked to oxidative stress, autophagy, ferroptosis, and lysosome function. We observed that most neurodegeneration- ...<|separator|>
[57]
Autophagy, aging, and age-related neurodegeneration - ScienceDirect
Aug 29, 2024 · Autophagy inhibition also induces neuronal and glial senescence, a phenomenon that occurs with increasing age in non-diseased brains as well as ...
[58]
Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases
As the brain ages, the effects of oxidative stress on mtDNA may lead to mutations and deletions and subsequently impair the OXPHOS complexes, increase ROS ...
[59]
Brain aging and neurodegeneration: from a mitochondrial point of view
Taken together, these findings emphasize that brain aging is marked by (i) a decrease in antioxidant defenses, (ii) an increased oxidative stress, and (iii) ...
[60]
Mitochondrial Dysfunction as the Major Basis of Brain Aging - PMC
Mitochondrial Dysfunction as the Major Basis of Brain Aging. Stephen C ... mechanism in Alzheimer's disease. Alzheimers Dement. 2018;4:575–590. doi ...
[61]
Mitochondrial Dysfunction during Brain Aging: Role of Oxidative ...
Mitochondrial dysfunction and oxidative stress are two interdependent and reinforcing damage mechanisms that play a central role in brain aging.
[62]
Mitochondrial Oxidative Stress and Energy Metabolism
Aug 4, 2021 · Furthermore, epigenetic modifications have been shown to greatly influence oxidative stress and mitochondrial dysfunction during aging [8].
[63]
Energy Metabolism and Brain Aging: Strategies to Delay Neuronal ...
Apr 21, 2025 · However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and ...
[64]
Mitochondrial Energy Metabolism and Redox Signaling in Brain ...
A decrease in the mitochondrial energy-transducing capacity is a common feature of brain aging and neurodegeneration and is associated with a progressive ...
[65]
Energy Metabolism and Inflammation in Brain Aging and ...
This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and ...<|separator|>
[66]
Mechanisms of DNA damage‐mediated neurotoxicity in ...
May 2, 2022 · Neurons are highly susceptible to DNA damage accumulation due to their large energy requirements, elevated transcriptional activity, ...The Dna Damage Response... · Dna Repair Syndromes As... · Dna Damage Induces...<|separator|>
[67]
Cell cycle-dependent and -independent telomere shortening ...
Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative ...
[68]
Telomere shortening induces aging-associated phenotypes in ...
Nov 21, 2023 · Motor neurons with shortened telomeres show age-dependent phenotypes. Short telomeres are considered one of the primary hallmarks of aging, and ...
[69]
Telomere length and human hippocampal neurogenesis - Nature
Sep 13, 2020 · Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and ...
[70]
Activated or Impaired: An Overview of DNA Repair in ...
Specifically, key enzymes involved in base excision repair are likely impaired in Alzheimer's disease and amyotrophic lateral sclerosis but activated in ...
[71]
DNA repair deficiencies and neurodegeneration - ScienceDirect.com
Neurodegeneration occurs in a variety of DNA repair deficiency diseases. Classical proteopathies are linked to DNA damage and defects in DNA repair.
[72]
Human Brain Aging is Associated with Dysregulation of Cell-Type ...
Jun 3, 2024 · We show here that neurons show age-associated DNA methylation changes even though they are largely post-mitotic. Therefore, epigenetic drift ...
[73]
Epigenetic regulation of aging: implications for interventions ... - Nature
Nov 7, 2022 · These aging-associated epigenetic changes include DNA methylation, histone modification, chromatin remodeling, non-coding RNA (ncRNA) regulation ...
[74]
Aging effects on DNA methylation modules in human brain and ...
Oct 3, 2012 · Age-related DNA methylation changes in the human cerebral cortex are known to involve differentiated neurons [27]. But future follow-up ...
[75]
DNA methylation analysis on purified neurons and glia dissects age ...
Jul 25, 2018 · In general, we observe a deep interplay between DNA methylation changes associated with aging, with cell-type and with disease progression. ...
[76]
Targeting neuronal epigenomes for brain rejuvenation - EMBO Press
Jul 15, 2024 · This review discusses the current evidence that identifies neuronal epigenetic aging as a driver of cognitive decline and a promising target of brain ...
[77]
Age-related epigenetic regulation in the brain and its role in ... - NIH
These variations in observed AD-associated epigenetic changes could result from differential changes in DNA methylation in different regions of the genome in AD ...
[78]
Transcriptional and Epigenetic Regulation in the Aging Brain
We described the first genome-wide expression profile of the aging human brain, providing evidence for a coherent “signature”of gene expression changes that ...Missing: shifts | Show results with:shifts
[79]
Epigenetics of the developing and aging brain: Mechanisms that ...
Epigenetic marks, such as DNA methylation and histone modifications, provide mechanisms by which early events can influence development, cognition, and health ...
[80]
Ageing and the brain - PMC - PubMed Central - NIH
The neurotransmitters most often discussed with regard to ageing are dopamine and serotonin. ... Other factors that have been implicated in the ageing brain ...
[81]
Disturbed Neurotransmitter Transporter Expression in Alzheimer ...
An imbalance of different neurotransmitters – glutamate, acetylcholine, dopamine, and serotonin - has been proposed as the neurobiological basis of behavioral ...<|separator|>
[82]
Hallmarks of Brain Aging: Adaptive and Pathological Modification by ...
Excitatory imbalances occur in the aging brain as a result of impaired GABAergic signaling, particularly reduced signaling via GABA-A receptors (Heise et al., ...
[83]
Altered Calcium Homeostasis in Old Neurons - Brain Aging - NCBI
In the intervening years, the role and participation of mitochondria in cellular Ca2+ homeostasis became clearer, and this relationship came to be included ...
[84]
Ageing in the brain: mechanisms and rejuvenating strategies
Jun 24, 2023 · The major causes of neuronal calcium dysregulation during ageing are ER stress, altered mitochondria homeostasis, dysregulated calcium channels' ...
[85]
Calcium signaling in neurodegeneration
May 6, 2009 · Calcium homeostasis disruption implicates several mechanisms, such as alterations of calcium buffering capacities, deregulation of calcium ...Increased Vulnerability To... · Disruption Of Mitochondrial... · App, Tau, And Calcium...
[86]
Expansion of the calcium hypothesis of brain aging and Alzheimer's ...
Mar 27, 2007 · Evidence accumulated over more than two decades has implicated Ca2+ dysregulation in brain aging and Alzheimer's disease (AD), giving rise to ...<|separator|>
[87]
Age-Related Deficits in Memory Encoding and Retrieval in Word List ...
Nov 30, 2018 · We find that ageing is associated with reduced total recall, especially for sequences with associated words.
[88]
Hippocampal formation size predicts declining memory performance ...
These results indicate HF atrophy may be a risk factor for accelerated memory dysfunction in normal aging. NEUROLOGY 1996;47: 810-813. Radiographically evident ...
[89]
Rates of hippocampal atrophy correlate with change in clinical ...
Conclusion: Rates of hippocampal atrophy match both baseline cognitive status and the change in cognitive status over time in elderly persons who lie along the ...Missing: deficits empirical
[90]
Age-related differences in encoding-retrieval similarity and their ...
Jul 12, 2021 · We posited that older adults would exhibit age-related reductions in encoding-retrieval similarity, particularly in visual and temporal regions, ...Missing: consolidation | Show results with:consolidation
[91]
Atrophy of hippocampal subfields relates to memory decline during ...
Dec 12, 2023 · It has been well documented that atrophy of hippocampus and hippocampal subfields is closely linked to cognitive decline in normal aging.Missing: deficits empirical
[92]
Aging effects on the encoding/retrieval flip in associative memory
Mar 12, 2024 · Results: According to our hypothesis, the results showed a significant age-related decline in the retrieval performance in the old group.
[93]
Age-Related Decline in Controlled Retrieval: The Role of the PFC ...
Increasing age leads to decreased prefrontal function, which decreases executive control, in turn blocking (perpendicular line) controlled memory retrieval.
[94]
[PDF] Memory Encoding and Retrieval in the Aging Brain
We conclude that, at the current state of knowledge, encoding deficiencies are more important than retrieval deficits in understanding the causes of episodic ...
[95]
Memory quality modulates the effect of aging on ... - ScienceDirect.com
Apr 1, 2020 · Memory quality modulates the effect of aging on memory consolidation during sleep: Reduced maintenance but intact gain.
[96]
Sleep-dependent prospective memory consolidation is impaired ...
Existing literature suggests that sleep-dependent memory consolidation is impaired in older adults but may be preserved for personally relevant information.Methods · Prospective Memory Task · Prospective Memory...<|separator|>
[97]
Consolidation in older adults depends upon competition between ...
Our findings demonstrate that a cross-network based approach can further the understanding of the neural underpinnings of aging-associated memory decline.
[98]
Age-related decline in bottom-up processing and selective attention ...
Decline in cognitive performance in healthy old-old adults has been linked to decreases in working memory capacity, slowing of perceptual processing, and ...
[99]
Evidence for an age-related decline in feature-based attention
The study found that older participants had more difficulty filtering out distracters based on features, likely due to a decrease in top-down suppression.
[100]
Age-Related Decline in Disengaging Spatial Attention in ... - MDPI
These results suggest that aging is associated with a greater difficulty in disengaging endogenous attention from the central, uninformative cue.
[101]
Older yet sharp: No general age-related decline in focusing attention.
Our results are inconsistent with the claim that aging is associated with either domain-specific or domain-general decline in focused attention.
[102]
Language Changes Associated with Aging - Oxford Academic
In this chapter we review literature on age-related changes in lexical retrieval and sentence processing, considering, in particular, clinically relevant ...
[103]
Sounds, Words, Sentences: Age-Related Changes Across Levels of ...
Age-related changes in sensory, lexical, and sentence processing were examined and compared using event-related potentials (ERPs) recorded as young and ...
[104]
(PDF) How aging and bilingualism influence language processing
Aug 8, 2025 · Overall, research on language comprehension in older healthy adults show that it is more preserved than language production. Bilingualism has ...Missing: reviewed | Show results with:reviewed<|separator|>
[105]
Age-Related Changes in Spatial Navigation Are Evident by Midlife ...
Together, our findings indicate that age-related changes in navigation ability and strategy are evident as early as midlife and that path-integration ability is ...
[106]
The Aging Navigational System - PMC - NIH
Aging causes a progressive loss of navigational abilities, including difficulties in computing spatial information, forming memory traces, and planning ...
[107]
Aging and spatial cues influence the updating of navigational ...
Aug 7, 2019 · It was recently found that older adults are impaired in updating spatial representations in small, bi-dimensional layouts. Because performance ...
[108]
Spatial memory and navigation in ageing: A systematic review of ...
Declines in spatial memory and navigation occur during the course of normal ageing due to the impact of age on the hippocampus and can serve as an easily ...
[109]
Multisensory Integration and Aging - The Neural Bases of ... - NCBI
Another logical hypothesis is that older adults show enhanced multisensory integration because they are unable to use selective attention to filter incoming ...LARGER TIME WINDOW OF... · DEFICITS IN ATTENTIONAL...
[110]
Impaired Multisensory Integration Predisposes the Elderly People to ...
Apr 28, 2020 · Accurate assessment of multisensory integration can help the elderly identify the impaired balance function and minimize the risk of fall.
[111]
Multisensory integration precision is associated with better cognitive ...
Integration across the senses also changes with age, yet the link between multisensory perception and cognitive ageing is poorly understood.
[112]
Aging-associated sensory decline and Alzheimer's disease
Dec 4, 2024 · Multisensory decline is common as people age, and aging is the primary risk of Alzheimer's Disease (AD). Recent studies have begun to shed ...
[113]
Limited Effects of Set Shifting Training in Healthy Older Adults - PMC
Mar 23, 2017 · Our ability to flexibly shift between tasks or task sets declines in older age. As this decline may have adverse effects on everyday life of ...
[114]
Factor analysis of attentional set-shifting performance in young and ...
Aug 12, 2011 · Executive dysfunction is likely to be a major contributor to the cognitive deficits that are observed with aging because the frontal lobes that ...
[115]
Neural structures underlying set-shifting: Roles of medial prefrontal ...
Impaired attentional set-shifting and inflexible decision-making are problems frequently observed during normal aging and in several psychiatric disorders.
[116]
Memory Decline and Behavioral Inflexibility in Aged Mice ... - Frontiers
Sep 3, 2019 · Aged mice display memory impairments, behavioral inflexibility, and synaptic plasticity failure. (A–C) Compared to young mice, performance of ...
[117]
The Theory Behind the Age-Related Positivity Effect - PMC - NIH
Sep 27, 2012 · The positivity effect refers to a relative preference in older adults (compared to younger adults) for positive over negative material in cognitive processing.
[118]
The age-related positivity effect in cognition: A review of key findings ...
Older adults are relatively more positive and/or less negative in their cognitive processing. This is known as the positivity effect.Abstract · Socioemotional Selectivity... · Positivity Effects In The...
[119]
Age and emotion regulation in daily life: Frequency, strategies ... - NIH
Older adults report generally high levels of emotional well-being despite normative declines in cognitive and physical functioning (Charles & Carstensen, 2010).
[120]
Full article: Age differences in emotion regulation strategy use and ...
Sep 21, 2023 · Older adults exhibited more frequent acceptance use, less frequent distraction use, and less flexibility in the responsiveness of strategies ...
[121]
Age-related reductions in arousal-enhanced memory are moderated ...
Sep 19, 2023 · We found the impact of emotional arousal on memory was reduced with age, especially for older adults who habitually suppress their emotions.
[122]
The positivity effect: a negativity bias in youth fades with age - NIH
Aug 5, 2017 · Relative to younger adults, older adults attend to and remember positive information more than negative information.
[123]
The genetics of cognitive ability and cognitive ageing in ... - PubMed
Heritability studies indicate that genetic variants strongly influence cognitive ability differences throughout the lifespan, including in old age.
[124]
A meta-analysis of heritability of cognitive aging - PubMed Central
Our findings, based upon evaluating 27 reports in the literature, suggest that verbal ability demonstrated declining heritability after age 60.
[125]
Genome-wide analysis of brain age identifies 59 associated loci and ...
Oct 3, 2025 · Here we conducted an in-depth genomic analysis of the brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in ...
[126]
Genome-wide analysis of brain age identifies 25 associated loci and ...
Dec 29, 2023 · Here, we investigated the genetic architecture of brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in ...
[127]
ApoE in Alzheimer's disease: pathophysiology and therapeutic ...
Nov 8, 2022 · While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene ...
[128]
APOE ε4 allele accelerates age-related multi-cognitive decline and ...
Jun 22, 2020 · Advanced age and apolipoprotein E (APOE) ε4 allele are both associated with increased risk of the Alzheimer's disease (AD).
[129]
Impact of APOE, Klotho, and sex on cognitive decline with aging
Even healthy carriers of the APOE ε4 gene have been reported to experience accelerated cognitive decline compared to noncarriers (8–10), along with notable ...
[130]
Impact of Apolipoprotein E ε4 in Alzheimer's Disease
Aug 23, 2024 · The apolipoprotein E (APOE) ε4 allele is a genetic factor known to increase AD risk and exacerbate brain atrophy and its symptoms.
[131]
Neuropathology-Independent Association Between APOE Genotype ...
Jan 20, 2023 · In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD ...Abstract · Cognitive Outcome Measures · Statistical Analyses
[132]
Rate of brain aging and APOE ε4 are synergistic risk factors for ...
May 27, 2019 · Advanced age and the APOE ε4 allele are the two biggest risk factors for Alzheimer's disease (AD) and declining cognitive function.
[133]
Apolipoprotein E and Alzheimer's disease - ScienceDirect.com
Individuals carrying APOE ε2 alleles have lower AD risk and those carrying APOE ε3 alleles have neutral risk. APOE is a lipoprotein which functions in lipid ...Review · 3. Apoe And The Brain · Conflicts Of Interest<|separator|>
[134]
Impact of Apolipoprotein E gene polymorphism during normal and ...
While APOE4 has a deleterious effect on the onset and progression of AD as well as on cognition during pathological aging [187], APOE2 - the rarest allele of ...Apoe And Antagonistic... · Apoe Polymorphism In Normal... · Apoe During Pathological...
[135]
APOE Alleles and Diet in Brain Aging and Alzheimer's Disease - PMC
Younger obese individuals with APOE4 have an increased risk of metabolic and vascular disease that negatively affects cognitive functions later in life. In ...
[136]
Consensus statement on exploring the Nexus between nutrition ...
Jul 25, 2025 · The majority of observational studies showed that the MIND diet is associated with better global cognitive function and possibly specific ...
[137]
Trial of the MIND Diet for Prevention of Cognitive Decline in Older ...
Jul 18, 2023 · Previous meta-analyses of diet trials have shown mixed results and generally do not affirm the beneficial effects of diet on cognition that were ...
[138]
In Pursuit of Healthy Aging: Effects of Nutrition on Brain Function
May 10, 2021 · A meta-analysis encompassing 15 trials and 6480 participants demonstrated that diet interventions (primarily based on the adoption of a ...
[139]
Effects of Exercise on Cognitive Performance in Older Adults
Among participants who were physically active, there was a 28% reduction in risk of dementia and a 45% reduction in Alzheimer's disease [11]. A later meta- ...
[140]
a systematic umbrella review and meta-meta-analysis
Executive function. Exercise was associated with improvements in executive function across all age groups, with the largest benefits observed in children ...
[141]
Physical Activity and Cognitive Decline Among Older Adults
Feb 1, 2024 · This systematic review and meta-analysis found that the association between physical activity and cognitive decline was very small, with no ...
[142]
https://www.cell.com/trends/neurosciences/fulltext/S0166-2236%252824%252900062-6
[143]
Association Between Sleep Duration and Cognitive Decline
Sep 21, 2020 · In this pooled cohort study, an inverted U-shaped association between sleep duration and global cognitive decline was found.<|control11|><|separator|>
[144]
Associations among sleep quality, sleep duration, and Alzheimer's ...
Mar 27, 2025 · This study aimed to clarify whether sleep quality or sleep duration affect amyloid beta (Aβ) and tau levels in plasma, cerebrospinal fluid (CSF), and positron ...
[145]
Poor sleep health is associated with older brain age - The Lancet
Sep 30, 2025 · Poor-quality sleep has been linked to increased dementia risk. We investigated the relationship between healthy sleep pattern and older ...
[146]
Improvement in sleep duration was associated with higher cognitive ...
Oct 20, 2020 · A change from short sleep duration (SSD) to moderate sleep duration (MSD) was associated with better global cognition scores.
[147]
Sleep quality and sleep duration predict brain microstructure among ...
May 1, 2023 · Although poor sleep quality and extreme sleep durations have been associated with brain atrophy and dementia, it is unclear whether sleep ...
[148]
Sex Differences in Brain Aging and Predictors of Neurodegeneration ...
In summary, we found widespread sex differences in the rates of regional volume loss, with men showing faster rates of neurodegeneration. We also found sex ...
[149]
Sex differences in healthy brain aging are unlikely to explain ... - PNAS
We found modest but systematic sex differences in age-related brain decline. Men showed decline in a greater number of brain regions, including multiple ...
[150]
Sex Differences in Cognitive Decline Among US Adults
Feb 25, 2021 · Women, compared with men, had significantly faster declines in global cognition and executive function, but not memory.
[151]
Sex and gender differences in cognitive resilience to aging and ...
Jul 5, 2024 · Hence, in the context of pathological aging, women with mild cognitive impairment (MCI) showed greater cognitive decline than men (as measured ...SEX AND GENDER... · MODIFIABLE AND... · SEX DIFFERENCES IN BRAIN...
[152]
Genetics of Alzheimer's disease: an East Asian perspective - Nature
Jun 1, 2022 · APOE genotypes are a well-established genetic risk factor in AD, with the East Asian population having a higher risk of AD associated with the ...
[153]
Alzheimer's Disease Genetics Fact Sheet | National Institute on Aging
Mar 1, 2023 · Genetic variations are one of several possible risk or protective factors for Alzheimer's disease. Learn about genetic variations that are ...
[154]
Racial differences in Alzheimer's disease unveiled - WashU Medicine
African-Americans may be twice as likely as Caucasian Americans to develop Alzheimer's disease, but nobody knows why because studies investigating the ...
[155]
Ethnic Differences in Dementia and Alzheimer's Disease - NCBI - NIH
This presents the potential for a major public health issue because ethnic minorities may be at higher risk for AD and dementia than non-Hispanic whites.
[156]
Assessing the lack of diversity in genetics research across ...
Jun 21, 2024 · Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study ...
[157]
Centenarian Study Uncovers Gene Variants That Shield Against ...
Jul 18, 2024 · The researchers found that people who reach age 100 without showing signs of Alzheimer's are enriched with genetic variants that help protect ...
[158]
Human longevity and Alzheimer's disease variants act via microglia ...
Jan 9, 2025 · Our work confirmed that genetic variation associated with Ad was enriched in gene networks expressed by microglia responding to ageing and ...
[159]
Lifetime Socioeconomic Status, Cognitive Decline, and Brain ...
Feb 21, 2025 · Higher SES, mainly in adulthood, was associated with better cognitive function, less cognitive decline, and better brain characteristics.
[160]
Lifetime Socioeconomic Status, Cognitive Decline, and Brain ... - NIH
Feb 21, 2025 · Higher SES, mainly in adulthood, was associated with better cognitive function, less cognitive decline, and better brain characteristics.
[161]
Lifestyle changes boost brain health - UC Davis Health
Sep 24, 2025 · Everyday lifestyle choices can protect brain health in older adults, according to new results from the U.S. POINTER Study, a two-year clinical ...
[162]
Lifestyle Choices and Brain Health - PMC - NIH
The areas to be discussed are: mental well-being, exercise, cognitively stimulating activities, sleep, nutrition, and social connectedness.
[163]
Socioeconomic status impacts cognitive and socioemotional ...
Apr 11, 2022 · Socioeconomic status (SES) negatively impacts cognitive and executive functioning in older adults, yet its effects on socioemotional abilities have not been ...
[164]
Effects of Lifestyle Factors on Cognition in Minority Population of ...
Mar 15, 2022 · These lifestyle factors include social engagement, physical activity, both aerobic and strength training, dietary intake, sleep and stress. This ...Missing: overriding | Show results with:overriding
[165]
Atrophy of hippocampal subfields relates to memory decline during ...
Dec 11, 2023 · It has been well documented that atrophy of hippocampus and hippocampal subfields is closely linked to cognitive decline in normal aging.Abstract · Introduction · Materials and methods · Discussion
[166]
Brain atrophy in Alzheimer's Disease and aging - ScienceDirect.com
This Review aims to describe the main MRI findings on GM and WM ... Among the MRI markers, hippocampal atrophy is the one best positioned for clinical use.
[167]
Aging and Cerebral Glucose Metabolism: 18F-FDG-PET/CT Reveals ...
Oct 12, 2023 · Monitoring changes in AG via positron emission tomography (PET) have shown a drastic reduction in glucose metabolism, leading to the use of AG ...
[168]
PET imaging of neural activity, β-amyloid, and tau in normal brain ...
Mar 5, 2021 · We reviewed recent literature on PET-based imaging of normal human brain aging in terms of neural activity, Aβ, and tau.
[169]
18F-FDG-PET Detects Drastic Changes in Brain ... - Frontiers
Jan 7, 2019 · 18 F-FDG-PET is used as a functional biomarker for AD as patients show an early and progressive reduction of cerebral glucose metabolism.
[170]
White matter microstructure across the adult lifespan: A mixed ...
Jan 1, 2021 · The macro- and microstructural architecture of human brain white matter undergoes substantial alterations throughout development and ageing.
[171]
Signatures of white-matter microstructure degradation during aging ...
Feb 25, 2021 · Our results show that age is associated with a decline in cognitive performance and a degradation in white matter integrity.
[172]
Analysis of Brain Structural Connectivity Networks and White Matter ...
Jan 30, 2022 · The data were analyzed using an advanced approach to assess both white matter microstructural integrity and structural connectivity.Abstract · Introduction · Materials and Methods · Discussion
[173]
Advanced Imaging Techniques (PET, fMRI, DTI) in Early Detection of ...
Jul 10, 2025 · PET, fMRI, and DTI are valuable tools for the early diagnosis of neurodegenerative diseases. These techniques can identify structural and ...
[174]
The Repeatable Battery for the Assessment of Neuropsychological ...
These data suggest that the RBANS is effective at both detecting and characterizing dementia of different etiologies. Publication types. Clinical Trial. MeSH ...
[175]
Regression-Based Normative Formulae for the Repeatable Battery ...
Aug 18, 2015 · The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has become a popular cognitive screening instrument, particularly ...
[176]
Repeatable battery for the assessment of neuropsychological status ...
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated with commonly used biomarkers of Alzheimer's disease (AD) ...
[177]
The CERAD Neuropsychological Battery Total Score and the ... - NIH
To establish the CERAD neuropsychological battery as a valid measure of cognitive progression in Alzheimer's disease (AD) by deriving annualized CERAD Total ...
[178]
CERAD (Consortium to Establish a Registry for Alzheimer's Disease ...
CERAD-NAB can identify mild cognitive impairment, facilitate differential dementia diagnosis, determine cognitive effects of naturally occurring and ...
[179]
A normative study of total scores of the CERAD neuropsychological ...
This study aimed to investigate the influences of age, education, and gender on the two total scores (TS-I and TS-II) of the Consortium to Establish a Registry ...
[180]
Neuropsychological Assessment - StatPearls - NCBI Bookshelf - NIH
Evaluations can vary from less than one hour to 6 to 8 or more hours of direct face-to-face examination, depending on the information sought and the patient's ...
[181]
The most frequently used tests for assessing executive functions in ...
There are numerous neuropsychological tests for assessing executive functions in aging, which vary according to the different domains assessed.<|separator|>
[182]
Neuropsychological tests for predicting cognitive decline in older ...
Results suggest RCFT Retention and Buschke Delay may be useful in predicting cognitive decline.
[183]
Diagnostic value of digital clock drawing test in comparison ... - Nature
Mar 5, 2019 · The CERAD neuropsychological assessment battery total score detects and predicts Alzheimer disease dementia with high diagnostic accuracy. The ...Introduction · Results · Discussion<|separator|>
[184]
Neuropsychological Evaluations in Adults - AAFP
Jan 15, 2019 · The tests are typically standardized using large normative samples of healthy age-matched individuals, allowing the examiner to determine ...Abstract · Evidence for... · Referring for a...
[185]
Robust norms for selected neuropsychological tests in older adults
The current study provided longitudinal robust norms for individuals age 70 years and older for several neuropsychological tests.
[186]
DNA methylation age of human tissues and cell types
I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types.
[187]
Accelerated epigenetic age is associated with whole-brain ... - Nature
Apr 26, 2024 · The first epigenetic clock, Horvath's multi-tissue age estimator, yields epigenetic age estimates highly correlated with chronological age.<|separator|>
[188]
THE ASSOCIATION OF EPIGENETIC CLOCKS IN BRAIN TISSUE ...
Epigenetic clocks have been noted as the most successful aging biomarkers yet. Although the prevalence of neurodegenerative diseases of aging, such as ...
[189]
Epigenetic clocks and DNA methylation biomarkers of brain health ...
Jun 18, 2025 · We focus on epigenetic clocks, which can be applied across multiple tissues and organs to estimate biological ageing, as well as on blood-based epigenetic ...
[190]
Epigenetic clocks and DNA methylation biomarkers of brain health ...
Jun 18, 2025 · We focus on epigenetic clocks, which can be applied across multiple tissues and organs to estimate biological ageing, as well as on blood-based epigenetic ...
[191]
Cell-type specific epigenetic clocks to quantify biological age at cell ...
Dec 29, 2024 · Using brain and liver tissue as prototypes, we build and validate neuron and hepatocyte specific DNA methylation clocks, and demonstrate that ...
[192]
[PDF] Long-Read epigenetic clocks identify improved brain aging predictions
Oct 3, 2025 · All participants have been determined to be neurologically healthy, making these cohorts suitable for generalizable, ancestry-specific ...
[193]
Cell-type specific epigenetic clocks to quantify biological age at cell ...
Another example is brain, with early studies reporting correlations of an accelerated Horvath-clock [28] with neurodegenerative features (e.g. neurotic plaques ...
[194]
Association of a pace of aging epigenetic clock with rate of cognitive ...
Nov 23, 2024 · We previously found that a faster pace of aging was associated with declines in IQ from childhood to midlife, signs of early brain aging, and ...
[195]
Resample aggregating improves the generalizability of connectome ...
However, overfitting is a common problem with statistical models, which impedes model ... Predicting brain-age from multimodal imaging data captures cognitive ...
[196]
Current challenges and future directions for brain age prediction in ...
Aug 20, 2025 · Brain-age models face biases that can impact their accuracy, interpretability, and generalizability. These include age dependence, which can be ...
[197]
A review on brain age prediction models - ScienceDirect.com
Jan 15, 2024 · Different review papers may use varied criteria for evaluating and comparing brain age prediction models, leading to inconsistent assessments.
[198]
A systematic review of multimodal brain age studies - Cell Press
Apr 14, 2023 · Another dimension of model accuracy is age-related prediction bias, which is a well-known limitation of the brain age framework. 19. Smith ...
[199]
https://www.nature.com/articles/s43856-025-01100-5
[200]
A systematic review of multimodal brain age studies - NIH
Apr 14, 2023 · We conducted a systematic review of multimodal brain age studies to identify which neuroimaging features provided the largest added value.
[201]
Pitfalls in brain age analyses - PMC - NIH
Jul 9, 2021 · The MBAG is by no means a more accurate measure of an out‐of‐sample residual, or prediction error (i.e., the “brain age gap”). The BAG itself is ...
[202]
Current challenges and future directions for brain age prediction in ...
Aug 20, 2025 · Model training and validation are critical for robust brain-age prediction. Models trained on data that do not represent the target population ...
[203]
BrainAGE, brain health, and mental disorders: A systematic review
Limitations include the lack of diverse samples, multi-modal studies, and validation. •. The lack of longitudinal models restricts the validity of brainAGE as a ...
[204]
Brain age has limited utility as a biomarker for capturing fluid ... - eLife
Jun 13, 2024 · When used to capture fluid cognition, Brain Age likely fails to add substantially more information over and above chronological age and ...
[205]
A novel deep learning-based brain age prediction framework for ...
Jul 29, 2025 · Generalizability of a model is a critical factor in developing brain age prediction models. Scans from different scanner vendors or ...<|separator|>
[206]
Explainable brain age prediction: a comparative evaluation of ...
Dec 18, 2024 · A common limitation of regression models is the phenomenon known as regression toward the mean [48, 49], which in the context of brain age ...
[207]
Cognitive reserve over the life course and risk of dementia - NIH
Apr 12, 2024 · Keywords: cognitive reserve, dementia, life course, meta-analysis, systematic review ... Sex, education, work-related physical activity, leisure ...
[208]
Leisure Activities and the Risk of Dementia in the Elderly
Like education, participation in leisure activities may lower the risk of dementia by improving cognitive reserve. In observational studies, elderly persons who ...
[209]
Association of lifelong exposure to cognitive reserve-enhancing ...
In this study, cumulative exposure to reserve-enhancing factors over the lifespan was associated with reduced risk of dementia in late life.
[210]
A lifespan perspective on cognitive reserve and risk for dementia - NIH
Jun 4, 2025 · We addressed whether higher education plays a causal role in reducing dementia risk by comparing two indices of cognitive reserve: education and young adult ...2.4. Dementia Ascertainment · 3. Results · 4. Discussion
[211]
Cognitive reserve is associated with education, social determinants ...
Jan 28, 2025 · Better cognitive reserve was associated with better cognitive function over mean 6.7 years follow-up (range 4-9 years); and the association for ...
[212]
Senolytic therapy alleviates physiological human brain aging and ...
Nov 13, 2023 · Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic ...
[213]
Senolytic Intervention Improves Cognition, Metabolism, and ...
Jul 2, 2024 · We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APP NL-F/NL-F mice.
[214]
Senolytic therapy is neuroprotective and improves functional ...
Senolytic drug therapy ablates senescent cells and reduces pro-inflammatory SASP levels in the brain long-term after TBI. We next examined whether ...
[215]
Senolytic Treatment Attenuates Global Ischemic Brain Injury and ...
Jun 18, 2025 · We aim to investigate the effects of combined senolytics Dasatinib plus Quercetin (D&Q) treatment in GCI and the underlying mechanisms in a mouse model.
[216]
Failure of senolytic treatment to prevent cognitive decline in a female ...
May 15, 2024 · Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function ...
[217]
A pilot study of senolytics to improve cognition and mobility in older ...
Feb 25, 2025 · Studies have demonstrated that co-administration of Dasatinib and Quercetin improved aspects of both physical and cognitive function in mice.
[218]
NAD+ in Brain Aging and Neurodegenerative Disorders - Cell Press
Oct 1, 2019 · Emerging evidence suggests NAD+ depletion in brain cells is common during aging and is accentuated in many neurodegenerative disorders including ...Nad In Brain Aging And... · Nad Synthesis And Metabolism · Main Text<|control11|><|separator|>
[219]
A systematic review of the therapeutic potential of nicotinamide ...
Mar 3, 2025 · Studies have revealed that treatment with NAD + rescues cognitive deficits by inhibiting inflammation, oxidative stress, and apoptosis and improving ...
[220]
A randomized placebo-controlled trial of nicotinamide riboside in ...
Nov 23, 2023 · Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some ...
[221]
Cognitive and Alzheimer's disease biomarker effects of oral ...
Jan 15, 2025 · Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative ...
[222]
Therapeutic potential of boosting NAD+ in aging and age-related ...
Emerging evidence implicates that elevation of NAD+ levels may slow or even reverse the aspects of aging and also delay the progression of age-related diseases.
[223]
Microglia: A pharmacological target for the treatment of age-related ...
As individuals age, microglia, the resident immune cells of the central nervous system (CNS), become less effective at preserving brain circuits.
[224]
Microglia in neurodegenerative diseases: mechanism and potential ...
Sep 22, 2023 · Production of neuroinflammation may trigger α-syn oligomerization, leading to a harmful cycle of microglial activation. Subsequent ...
[225]
Immune modulation to treat Alzheimer's disease
Mar 31, 2025 · This review provides an overview of immunomodulatory therapeutics currently being developed for AD, including small molecules, biologics, novel compounds, and ...
[226]
Cellular senescence, DNA damage, and neuroinflammation in the ...
May 9, 2024 · In this review, we summarize recent advances in the immunology of normal brain aging that is caused by the accumulation of DNA damage and ...
[227]
The role of neuroinflammation in neurodegenerative diseases
This review reveals the major neuroinflammatory signaling pathways associated with neurodegeneration. Additionally, it explores promising therapeutic avenues.
[228]
Role of neuroinflammation in neurodegeneration development
Jul 12, 2023 · Here we comprehensively review the factors affecting neuroinflammation and the major inflammatory signaling pathways involved in the pathogenicity of ...
[229]
Advances in mesenchymal stem cell and exosome-based therapies ...
Jul 26, 2025 · Exosomes secreted by mesenchymal stem cells delay brain aging by upregulating SIRT1 expression. Sci. Rep. 2023;13:13213. https://doi.org ...
[230]
Recent progress in stem cell and immune cell-based interventions ...
This treatment improved the cognitive and physical functions of naturally aging rats and prolonged their lifespan by 23.4% (AM-MSCs) and 31.3% (AD-MSCs), ...Introduction · Anti-aging of stem cells · Anti-aging of immune cells · Future outlook
[231]
https://www.sciencedaily.com/releases/2025/10/251023031631.htm
[232]
Stem Cell Advances Reshape Alzheimer's Research and Treatment
Sep 22, 2025 · A recent Phase 1 human trial demonstrated that MSC therapy reduced inflammation and tissue loss in the brain after a single injection. Advances ...
[233]
Epigenetic changes during aging and their reprogramming potential
New studies show that age-related epigenetic changes can be reversed with interventions such as cyclic expression of the Yamanaka reprogramming factors.
[234]
Chemically induced reprogramming to reverse cellular aging
A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of ...
[235]
Epigenetic reprogramming as a therapeutic strategy for ...
Sep 5, 2025 · Epigenetic reprogramming has emerged as a promising therapeutic strategy for neurodegenerative diseases by targeting reversible gene expression changes.Missing: reactivation | Show results with:reactivation
[236]
Brain aging shows nonlinear transitions, suggesting a midlife ...
Mar 3, 2025 · Importantly, we find that administering ketones, which can fuel neurons while bypassing insulin resistance, reverses brain aging effects.
[237]
Scientists Identify Critical “Midlife Window” for Preventing Age ...
Mar 5, 2025 · Groundbreaking research reveals metabolic interventions could help prevent cognitive aging. STONY BROOK, NY, March 5, 2025 – A landmark ...
[238]
Review The 'middle-aging' brain - ScienceDirect.com
In this way, middle age could offer an intervention point to prevent accelerating brain aging and cognitive decline. Cognitive changes of the middle-aged brain.
[239]
Life's Essential 8 and midlife trajectories in cognition and brain ...
Dec 23, 2024 · Poor CVH is related to accelerated brain aging across midlife, highlighting the need to screen for and improve CVH earlier to prevent adverse ...<|control11|><|separator|>
[240]
Inconsistencies and Controversies Surrounding the Amyloid ...
Sep 18, 2014 · There are many unresolved issues in the amyloid hypothesis. The field has pursued the idea that Aβ accumulation is the central cause of AD ...
[241]
Inconsistencies and controversies surrounding the amyloid ...
Sep 18, 2014 · We note several unresolved issues in the field including the presence of Aβ deposition in cognitively normal individuals, the weak correlation ...
[242]
The amyloid hypothesis is too good to be true - OAText
The extent of brain amyloid formation and the natural history of memory and mind problems are not even correlated in Alzheimer progression, therefore cannot be ...<|separator|>
[243]
Alzheimer's disease beyond amyloid: Can the repetitive failures of ...
In addition, temporal, spatial and quantal issues exist with regard to the presence of brain amyloid and AD incidence that have neither been adequately ...
[244]
Major Clinical Trials Failed the Amyloid Hypothesis of Alzheimer's ...
Mar 9, 2019 · Hence the amyloid hypothesis of AD pathogenesis has dominated anti-amyloid drug research and development for more than 30 years. We report ...
[245]
Anti-amyloid failures stack up as Alzheimer antibody flops - Nature
Apr 5, 2019 · At least four anti-amyloid antibodies have failed in phase III trials in different Alzheimer disease settings. Three BACE inhibitors and two γ- ...
[246]
The controversy around anti-amyloid antibodies for treating ...
Oct 23, 2024 · The long-running controversy over the safety and efficacy of anti-amyloid drugs (AADs) for treating Alzheimer's Disease (AD) has intensified.
[247]
Amyloid Hypothesis in Doubt as Newly Approved Drugs Hit Hurdles
Dec 16, 2024 · But the hypothesis gained new life over the next two years, as the FDA approved two more anti-amyloid antibodies—Leqembi in January 2023 and ...
[248]
Amyloid hypothesis: 20 years of failure in Alzheimer's research - PMC
We reviewed the data of past failures to determine how aducanumab and lecanemab might differ from the rest of this class of drugs.
[249]
Blots on a field? - Science
Jul 21, 2022 · Some adherents of the amyloid hypothesis are too uncritical of work that seems to support it, he says. “Even if misconduct is rare, false ideas ...
[250]
RETRACTED ARTICLE: A specific amyloid-β protein ... - Nature
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory. Sylvain Lesné,; Ming Teng Koh,; Linda Kotilinek,; Rakez Kayed ...
[251]
Alzheimer's scientist resigns after university finds 'data integrity ...
Feb 10, 2025 · The paper buoyed confidence in the so-called amyloid hypothesis of Alzheimer's, which holds that a brain buildup of amyloid proteins provokes a ...
[252]
How the 'amyloid mafia' took over Alzheimer's research - STAT News
including the sticky plaques thought to promote a ...
[253]
Is the Alzheimer's “Amyloid Hypothesis” Wrong? - Consensus
May 29, 2019 · Despite the supporting evidence, the amyloid hypothesis has several unresolved issues. One major criticism is the presence of Aβ deposits in ...