In a sample of nearly 3,000 older adults who took vision tests and cognitive tests during home visits, the risk of dementia was much higher among those with eyesight problems - including those who weren't able to see well even when they were wearing their usual eyeglasses or contact lenses. All of the older adults in the study were over the age of 71, with an average age of 77. They had their up-close and distance vision, and their ability to see letters that didn't contrast strongly with their background, tested by a visiting team member using a digital tablet. They also took tests of memory and thinking ability, and provided health information including any existing diagnosis of Alzheimer's disease or another form of dementia.

Just over 12% of the whole group had dementia. But that percentage was higher - nearly 22% - among those who had impaired vision for seeing up close. In addition, one-third (33%) of those with moderate or severe distance vision impairment, including those who were blind, had signs of dementia. So did 26% of those who had trouble seeing letters that didn't contrast strongly against a background. Even among those with a mild distance vision issue, 19% had dementia. After the researchers adjusted for other differences in health status and personal characteristics, people with moderate to severe distance vision issues were 72% more likely than those with no vision issues to have dementia.

Estimates of the association between visual impairment (VI) and dementia in the US population are based on self-reported survey data or measures of visual function that are at least 15 years old. Older adults are at high risk of VI and dementia so there is a need for up-to-date national estimates based on objective assessments. This secondary analysis of the 2021 National Health and Aging Trends Study (NHATS), a population-based, nationally representative panel study, included 3,817 respondents 71 years and older.

The weighted prevalence of dementia was 12.3% and increased with near VI (21.5%), distance VI (mild: 19.1%; moderate, severe, or blind: 32.9%), and contrast sensitivity (CS) impairment (25.9%). Dementia prevalence was higher among participants with near VI and CS impairment than those without (near VI prevalence ratio: 1.40; CS impairment prevalence ratio: 1.31) and among participants with moderate to severe distance VI or blindness (prevalence ratio: 1.72) after adjustment for covariates.

Thus in this survey study, all types of objectively measured VI were associated with a higher dementia prevalence. As most VI is preventable, prioritizing vision health may be important for optimizing cognitive function.

Microglia, the innate immune cells of the brain, influence Alzheimer's disease (AD) progression and are potential therapeutic targets. However, microglia exhibit diverse functions, the regulation of which is not fully understood, complicating therapeutics development. To better define the transcriptomic phenotypes and gene regulatory networks associated with AD, we enriched for microglia nuclei from 12 AD and 10 control human dorsolateral prefrontal cortices (7 males and 15 females, all 60 years or older) before single-nucleus RNA sequencing. Here we describe both established and previously unrecognized microglial molecular phenotypes, the inferred gene networks driving observed transcriptomic change, and apply trajectory analysis to reveal the putative relationships between microglial phenotypes.

This study identified 10 distinct microglia clusters from aged human brain. These included previously described homeostatic, senescent, and inflammatory microglia transcriptional phenotypes as well as additional clusters of transcriptional specification, which may give insight into AD pathogenesis, providing a platform for hypothesis generation. We describe the diversity of microglia clusters with endolysosomal gene signatures, one of which is enriched with nucleic acid recognition and interferon regulation genes. Inferred gene networks predict that individual clusters are driven by distinct transcription factors, lending further support for the functional diversity of clusters. Using trajectory inference analysis, we observed transitions in microglia phenotypes and predicted relationships that can be tested experimentally. AD cases were distinguished by the emergence of a subcluster expressing homeostatic genes that was characterized by altered transcription of genes involved in calcium activation, response to injury, and motility pathways.

Among the nuclei meeting criteria for a microglia transcriptomic signature, an 'aging signature' was observed in all clusters in this study, consistent with our older age cohort. Inflammaging may not only confound interpretations of gene expression profiles attributable to AD but may also contribute to the disease mechanisms hypothesized to drive AD. Additional studies exploring differences between younger controls and early-onset AD may also help to explore the aging, inflammaging, and AD-specific signatures.

A deafened adult cannot recover the ability to hear, because the sensory hearing cells of the inner ear don't regenerate after damage. In the non-sensory supporting cells of the inner ear, key genes required for conversion to sensory cells are shut off through a process known as epigenetic silencing. By studying how the genes are shut off, researchers can begin to understand how we might turn them back on to regenerate hearing.

Researchers explored when and how the progenitor cells of the inner ear gain the ability to form sensory hearing cells. The scientists pinpointed when progenitor cells acquire this ability: between days 12 and 13.5 of embryonic development in mice. During this window, the progenitor cells acquire the capacity to respond to signals from the master regulator gene Atoh1 that triggers the formation of sensory hearing cells later during development. What primes the progenitor cells to respond to Atoh1 are two additional genes, Sox4 and Sox11, that change the state of these cells.

In adult mice with damaged sensory cells in the inner ear, high levels of Sox4 and Sox11 activity increased the percentage of vestibular supporting cells that converted into sensory receptor cells - from 6 percent to 40 percent. "We're excited to continue exploring the mechanisms by which cells in the inner ear gain the ability to differentiate as sensory cells during development and how these can be used to promote the recovery of sensory hearing cells in the mature inner ear."

One important way that genes are shut off or "silenced" involves chemical compounds called methyl groups that bind to DNA and make it inaccessible. When the DNA that instructs a cell to become a sensory hearing cell is methylated, the cell cannot access these instructions. DNA methylation silences genes that promote conversion into sensory hearing cells, including the gene Atoh1 that is known to be a master regulator of inner ear development.

Researchers tested the extent of gene silencing in supporting cells from a chronically deafened mouse. They found that gene silencing was partially reversed, meaning that the supporting cells had the capacity to respond to signals to transform into sensory hearing cells. This finding has important implications: the loss of sensory hearing cells itself might partially reverse gene silencing in supporting cells in chronically deaf individuals. If so, the supporting cells of chronically deaf individuals might already be naturally primed to convert into sensory hearing cells.

Understanding the molecular basis of competence acquisition by the lineage-specific progenitor cells provides insights into tissue development and regeneration. The sensory epithelium of the inner ear represents a convenient model to study this process, as only two cell types - the mechanosensory hair cells and their associated supporting cells - are specified from a single pool of progenitors in this lineage. In the present manuscript, we uncover some of the mechanisms by which competence for mechanosensory receptor differentiation is acquired in the early organ of Corti progenitor cells. Specifically, we show that the two SoxC family members, Sox 4 and Sox11, establish a permissive chromatin landscape that allows the hair cell gene regulatory network to be activated upon differentiation cues.

Age-related hearing loss can significantly impact quality of life. One potential approach to restore hearing is to regenerate mechanosensory hair cells responsible for detecting sound by the conversion of neighboring supporting cells into new hair cells. However, mammalian supporting cells can only transdifferentiate during embryonic and early postnatal development, and this ability is lost before the onset of hearing. We show that supporting cells accumulate DNA methylation, a form of epigenetic silencing, to permanently shut off the hair cell gene program required for successful transdifferentiation. Blocking ten-eleven translocation (TET) enzyme activity extends the window in which transdifferentiation can occur. Moreover, the loss of hair cells by deafening partially reverses DNA methylation in supporting cells, suggesting one avenue for therapeutic intervention.

For years, scientists have known that the anti-aging hormone klotho, infusions of young blood, and exercise each improve brain function in older mice. But they didn't know why. Now, researchers have identified platelet factor 4 (PF4) - a small protein released by blood platelets - as a common denominator behind all three. Platelets are blood cells that normally release PF4 to alert the immune system and clot blood at wounds. The researchers found that PF4 also rejuvenates the old brain and boosts the young brain, potentially opening the door to new therapies that aim to restore brain function, if not tap into a fountain of youth.

In 2014, researchers found that blood plasma from young mice restored brain function in old animals. His team then found that young plasma contained much more PF4 than old plasma. Moreover, just injecting PF4 into old animals was about as restorative as young plasma. It calmed down the aged immune system in the body and the brain. Old animals treated with PF4 performed better on a variety of memory and learning tasks. "PF4 actually causes the immune system to look younger, it's decreasing all of these active pro-aging immune factors, leading to a brain with less inflammation, more plasticity and eventually more cognition. We're taking 22-month-old mice, equivalent to a human in their 70s, and PF4 is bringing them back to function close to their late 30s, early 40s."

A decade ago, researchers showed that the hormone klotho enhances brain function in young and old animals and also makes the brain more resistant to age-related degeneration. But klotho, injected into the body, never reached the brain. So, how? Researchers found that one connection was PF4, released by platelets after an injection of klotho. PF4 had a dramatic effect on the hippocampus, where memories are formed in the brain. In particular, PF4 enhanced the formation of new neural connections at the molecular level. It also gave both old and young animals a brain boost in behavioral tests.

Exercise can keep the mind sharp for decades. In 2019, researchers found that platelets released PF4 into the bloodstream following exercise. When they tested PF4 on its own, it improved cognition in old animals. "We can now target platelets to promote neurogenesis, enhance cognition, and counteract age-related cognitive decline."

Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments.

Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.

Unhealthy lifestyles and accrual of risk factors contribute to vascular dysfunction highlighted by cellular senescence and impaired synthesis and secretion of endothelium-derived vasoactive molecules. Genetic factors also participate in determining the dichotomy between cardiovascular health and disease. Nonetheless, very few gene polymorphisms proved to capture the divergence of cardiovascular clocks seen in high-risk individuals (HRIs) and long-living individuals (LLIs). Among them, the longevity variant (LAV) of the BPI Fold Containing Family B Member 4 (BPIFB4) gene, showed a preponderant impact on the cardiovascular system and prolonged life span, passing the validation of three geographically unrelated cohorts.

Carriers of the LAV-BPIFB4 gene express high levels of the encoded protein in the blood, circulating mononuclear cells, and vascular cells. Moreover, high levels of circulating BPIFB4 protein protected against carotid stenosis in human cohorts. Contrariwise, BPIFB4 is reportedly downregulated in the heart of patients with end-stage ischemic heart failure.

Importantly, we have provided substantial evidence for the possibility of transferring the healthy phenotype conferred by LAV-BPIFB4 to cardiovascular animal models, suggesting that temporary expression of an evolutionary successful human gene can halt and even reverse age-related damage. LAV-BPIFB4 gene therapy in mice demonstrated anti-atherosclerotic, anti-hypertensive, pro-angiogenic, and neuroprotective activities. Moreover, it improved frailty indices and diabetic and age-related cardiomyopathies, and rejuvenated the elderly vasculature. In addition, replicating the preserved immune function of centenarians, the LAV-BPIFB4 protein encouraged immunomodulatory responses by human myeloid cells.

Skeletal muscle function and regenerative capacity decline during aging, yet factors driving these changes are incompletely understood. Muscle regeneration requires a set of temporally coordinated transcriptional programs to drive myogenic stem cells to activate, proliferate, fuse to form myofibers, and to mature as myonuclei, restoring muscle function after injury. We assessed global changes in myogenic transcription programs distinguishing muscle regeneration in aged mice from young mice by comparing pseudotime trajectories from single-nucleus RNA sequencing of myogenic nuclei.

Aging-specific differences in coordinating myogenic transcription programs that are necessary for restoring muscle function occur following muscle injury, likely contributing to compromised regeneration in aged mice. Differences in pseudotime alignment of myogenic nuclei when comparing aged with young mice via dynamic time warping revealed that pseudotemporal differences become progressively more severe as regeneration proceeds. Disruptions in timing of myogenic gene expression programs may contribute to incomplete skeletal muscle regeneration and declines in muscle function as organisms age.

Young blood plasma is known to confer beneficial effects on various organs in mice and rats. However, it was not known whether plasma from young pigs rejuvenates old rat tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=613 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=1366 human tissue samples to the training data.

We employed these six rat clocks to investigate the rejuvenation effects of a porcine plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. An immunoglobulin G (IgG) N-glycosylation pattern shift from pro-to anti-inflammatory also indicated reversal of glycan aging. Overall, this study demonstrates that a young porcine plasma-derived treatment markedly reverses aging in rats according to epigenetic clocks, IgG glycans, and other biomarkers of aging.

It is widely reported that the mitochondrial membrane potential, ∆Ψm, is reduced in aging animals. It was recently suggested that the lower ∆Ψm in aged animals modulates mitochondrial bioenergetics and that this effect is a major cause of aging since artificially increased ∆Ψm in C. elegans increased lifespan. Here, I critically review studies that reported reduction in ∆Ψm in aged animals, including worms, and conclude that many of these observations are best interpreted as evidence that the fraction of depolarized mitochondria is increased in aged cells because of the enhanced activation of the mitochondrial permeability transition pore, mPTP.

Activation of the voltage-gated mPTP depolarizes the mitochondria, inhibits oxidative phosphorylation, releases large amounts of calcium and reactive oxygen species (ROS), and depletes cellular NAD+, thus accelerating degenerative diseases and aging. Since the inhibition of mPTP was shown to restore ∆Ψm and to retard aging, the reported lifespan extension by artificially generated ∆Ψm in C. elegans is best explained by inhibition of the voltage-gated mPTP. Similarly, the reported activation of the mitochondrial unfolded protein response by reduction in ∆Ψm and the reported preservation of ∆Ψm in dietary restriction treatment in C. elegans are best explained as resulting from activation or inhibition of the voltage-gated mPTP, respectively.

The adrenal gland is an essential endocrine organ that is situated above the kidneys and functions to produce essential steroid hormones including mineralocorticoids, glucocorticoids, and androgens. The adrenal is composed of two compartments of distinct embryological origin: the cortex and the medulla, which are surrounded by an outer mesenchymal capsule layer. In this review, we will focus on age-related changes specifically within the adrenal cortex, which is subdivided into three functionally and histologically distinct zones.

The outermost zone, the zona glomerulosa (zG), is responsible for the production of mineralocorticoids that regulate salt and water balance. The intermediate zone, the zona fasciculata (zF), produces glucocorticoids in response to adrenocorticotropin (ACTH) under the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Finally, the innermost zone, the zona reticularis (zR), produces adrenal androgens, including dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S. As we age, the adrenal gland undergoes changes that disrupt its ability to maintain homeostatic hormone levels, which can significantly affect overall health and well-being. Thus, researching adrenal aging and interventions to delay the onset of age-associated adrenal pathologies has the potential to help increase endocrine function and improve health span.

Studying the effects of aging on the normal adrenal gland is a challenging task. First, information on "healthy" aged human adrenal glands in the literature is scarce. While rodents are the most commonly used model organism to investigate these phenomena, standard laboratory strains lack a functional zR due to silencing of Cyp17a1 after birth, which limits our use of these models to study adrenal androgens. Moreover, the mouse adrenal cortex contains an additional X-zone. The functional significance of the X-zone is incompletely understood.

With increasing age, features such as reduced adrenal cortex size, altered zonation, and increased myeloid immune cell infiltration substantially alter the structure and function of the adrenal cortex. Many of these hallmark features of adrenal cortex aging occur both in males and females, yet are more enhanced in males. Hormonally, a substantial reduction in adrenal androgens is a key feature of aging, which is accompanied by modest changes in aldosterone and cortisol. These hormonal changes are associated with various pathological consequences including impaired immune responses, decreased bone health, and accelerated age-related diseases.

One of the most notable changes with adrenal aging is the increased incidence of adrenal tumors, which is sex dimorphic with a higher prevalence in females. Increased adrenal tumorigenesis with age is likely driven by both an increase in genetic mutations as well as remodeling of the tissue microenvironment. Novel antiaging strategies offer a promising avenue to mitigate adrenal aging and alleviate age-associated pathologies, including adrenal tumors.

Lipid metabolism plays crucial roles in cellular processes such as hormone synthesis, energy production, and fat storage. Older adults are at risk of the dysregulation of lipid metabolism, which is associated with progressive declines in the physiological function of various organs. With advancing age, digestion and absorption commonly change, thereby resulting in decreased nutrient uptake. However, in the elderly population, the accumulation of excess fat becomes more pronounced due to a decline in the body's capacity to utilize lipids effectively. This is characterized by enhanced adipocyte synthesis and reduced breakdown, along with diminished peripheral tissue utilization capacity.

Lipid metabolism disorder is one of the key pathogenic factors for the occurrence and development of a series of lipid-related chronic diseases. In general, lipid-related diseases include cardiovascular disease, type 2 diabetes, non-alcoholic fatty liver disease, and obesity, which seriously threaten public health. Given that changes in lipid metabolism occur in healthy older adults, it is important to note that these changes may contribute to pathological alterations. Therefore, understanding the role of lipid metabolism in the development of these diseases may provide new insights into their underlying mechanisms and facilitate the development of effective treatments and prevention for the elderly

Lifespan extension has independently evolved several times during mammalian evolution, leading to the emergence of a group of long-lived animals. Though the mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is shown as a central regulator of lifespan and aging, the underlying influence of mTOR pathway on the evolution of lifespan in mammals is not well understood. Here, we performed evolution analyses of 72 genes involved in the mTOR network across 48 mammals to explore the underlying mechanism of lifespan extension.

In our study, autophagy related genes were identified to be under positive selection (PRKCB, WDR24, NPRL3 and LAMTOR2) or convergent (ATP6V1H and SESN2) in long-lived species, or associated with maximum life span (LAMTOR4), suggesting that enhanced autophagy might be a potential mechanism for mammals to extend lifespan. Moreover, eight genes with evolutionary signals identified in long-lived species were cancer related genes, six of them were also associated with aging, suggesting that regulation of cancer and aging may be another important mechanism for extending lifespan. In conclusion, we identified 20 genes with significant evolutionary signals unique to long-lived species, which provided new insight into the lifespan extension of mammals and might bring new strategies to extend human lifespan.

Surgeons have transplanted a genetically engineered pig kidney that continues to function well after 32 days in a man declared dead by neurologic criteria and maintained with a beating heart on ventilator support. This represents the longest period that a gene-edited pig kidney has functioned in a human. The first hurdle to overcome in xenotransplants is preventing so-called hyperacute rejection, which typically occurs just minutes after an animal organ is connected to the human circulatory system. By "knocking out" the gene that encodes the biomolecule known as alpha-gal - which has been identified as responsible for a rapid antibody-mediated rejection of pig organs by humans - immediate rejection has been avoided. Additionally, the pig's thymus gland, which is responsible for educating the immune system, was embedded underneath the outer layer of the kidney to stave off novel, delayed immune responses. The combination of modifications has been shown to prevent rejection of the organ while preserving kidney function.

To ensure the body's kidney function was sustained solely by the pig kidney, both of the transplant recipient's native kidneys were surgically removed. One pig kidney was then transplanted and started producing urine immediately without any signs of hyperacute rejection. During the observation phase, intensive care clinical staff maintained the decedent on support while the pig kidney's performance was monitored and sampled with weekly biopsies. Levels of creatinine, a bodily waste product found in the blood and an indicator of kidney function, were in the optimal range during the length of the study, and there was no evidence on biopsy of rejection.

The kidney and thymus gland used in this procedure were procured from a GalSafe pig, an animal engineered by Revivicor Inc., a subsidiary of United Therapeutics Corporation. In December 2020, the U.S. Food and Drug Administration (FDA) approved the GalSafe pig as a potential source for human therapeutics, as well as a food source for people with alpha-gal syndrome, a meat allergy caused by a tick bite. While previous genetically engineered pig organ transplants have incorporated up to 10 genetic modifications, this latest study shows that a single-gene knockout pig kidney can still perform optimally for at least 32 days without rejection.

Extracellular vesicles (EVs) can be produced from red blood cells (RBCs). The EVs that originate from red blood cells (RBCEVs) have favourable characteristics for serving as an effective drug delivery platform. They are devoid of DNA and inherit their allogenic transfusion compatibility traits from RBCs, hence potentially providing safe, 'off-the-shelf' medication. In addition, RBCs can be readily collected from volunteers and stimulated with calcium ionophore to release large amounts of RBCEVs.

Since EVs are complex entities which act as carriers of biological agents that can modulate their target cells, applying them for therapeutic purposes requires an in-depth understanding of their interactions with these cells and the potential effects of their various components. In the case of RBCEVs, haemoglobin is the most abundant protein present. In human adults, haemoglobin is mainly present in the form of haemoglobin A. Haemoglobin is safe when carried by RBCs but it is toxic when released from RBCs into the bloodstream and interstitial space due to hemolysis. However, this toxicity of free haemoglobin can be neutralized by haptoglobin, a protein secreted from liver cells. This is because haemoglobin and haptoglobin form a complex that is rapidly processed by macrophages through the CD163 receptor. Upon internalization, the haemoglobin component of the complex is broken down, and the heme groups are processed by an enzyme called heme oxygenase 1 (HO-1).

HO-1 plays a protective role against atherosclerosis. This protective effect is speculated to stem from the catalytically enzymatic degradation of heme by HO-1. During the process, heme is broken down into ferrous ions, CO (which inhibits inflammation), and biliverdin (which has antioxidant properties). Thus we hypothesize that in RBCEVs, haemoglobin is protected in enclosed vesicles, preventing cytotoxicity. In addition, we speculate that the haemoglobin carried by RBCEVs exerts both anti-inflammatory and anti-atherosclerosis effects mediated via the HO-1 pathway when the EVs are taken up by macrophages.

In this study, we investigated the uptake of RBCEVs by macrophages. We also monitored the intracellular trafficking of RBCEVs and the fate of haemoglobin, their most abundant protein cargo. We found that RBCEVs were preferentially taken up by macrophages in the liver and spleen. The EVs then released heme into the cytoplasm via the heme transporter HRG1, which promoted the differentiation of the macrophages to a phenotype characterized by upregulated HO-1 expression, and prevented the accumulation of oxidized low-density lipoproteins (oxLDL) in these cells. This natural therapeutic characteristic of RBCEVs suggests their potential benefits in atherosclerosis treatment, especially when combined with other drug cargoes that can be loaded into and carried by these EVs. In addition, the anti-inflammatory properties of RBCEVs might be effective for the treatment of other inflammatory conditions.

CD8+ T lymphocytes are adaptive immune cells that, upon antigen recognition, undergo a complex differentiation process. In acute inflammatory responses, when antigen is effectively cleared, short-lived effector T cells undergo controlled apoptosis, while long-lived effector T lymphocytes differentiate into memory T cells, thus efficiently resolving the inflammatory reaction. However, during chronic inflammatory conditions, this natural resolution is impaired, and CD8+ T lymphocytes become exhausted or senescent, retaining a neurotoxic potential and contributing to several neurodegenerative diseases.

CD8+ T cells, reacting against self and non-self antigens are clonally expanded in all brain disorders discussed in this review, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. It is worth noting that although these disorders may have distinct causes, occurrence rates, and clinical presentations, they share common immunopathological characteristics. These include the circulating origin of central nervous system-invading CD8+ T lymphocytes, the clonal expansion of CD8+ T cells, and phenotypical traits that resemble senescence.

In the light of growing evidence suggesting that senescent and exhausted CD8+ T cells contribute to aging and various brain disorders, a promising therapeutic approach for these conditions may be represented by targeting deleterious functions of CD8+ T cells. Indeed, targeting senescent and exhausted CD8+ T cells may create a personalized neuroimmunotherapy, with the ultimate goal to rejuvenate T cells through tailored diagnostic and therapeutic protocols. Strategies such as epigenetic modulation and using senolytic compounds to induce apoptosis in senescent and exhausted CD8+ T cells may also be explored. Several studies are ongoing to prove the effectiveness of interventions targeting tissue-damaging senescent cells, which may slow, prevent, and alleviate disorders in preclinical models. The development of senolytic small molecules that can specifically eliminate senescent cells, may represent a promising strategy for treating multiple CD8+ T cell senescent-mediated disorders and age-related conditions in humans.

Researchers sampled 15 regions in both hemispheres of the brains of 59 female and male mice aged 3 to 27 months. They identified and ranked the top genes expressed by cells found in each region of the brain. They identified 82 genes that are frequently found and vary in concentration in 10 or more regions. The team used these genes to develop a common aging score, assessing how gene activity in different regions of the brain change with age. The researchers found that the white matter, which is found deep in the brain and contains nerve fibers protected by white-colored myelin, showed the earliest and most pronounced changes in gene expression for mice 12 and 18 months old. These mice are about as old, in mouse years, as a person in their 50s.

Past work has shown that aging disrupts an otherwise stable gene expression pattern in the brain, turning on genes that regulate inflammation and the immune response, and turning off genes responsible for protein and collagen synthesis. The inflammation and immune response affect the integrity of the myelin sheath, the insulation layer around nerves responsible for transmitting signals across the brain. "White matter has been a rather neglected area in aging research, which usually focuses on the neuron-dense regions like the cortex or hippocampus. The fact that white matter is emerging in our data as an area of particular vulnerability to aging opens up new and intriguing hypotheses."

Interventions to slow the genetic shift that leads to the decline in specific regions of the brain could be beneficial in addressing neurodegenerative disease as well as the general decline associated with aging. During the study, the team explored two interventions - caloric restriction and injections of plasma from young mice - to evaluate whether they protected against the region-specific shifts in gene expression. Each intervention began when the mice were 19 months old and lasted four weeks. The researchers found that the dietary intervention caused genes associated with circadian rhythms to turn on, while the plasma intervention turned on genes involved in stem cell differentiation and neuronal maturation that led to selective reversal of age-related gene expression. "The interventions appeared to act on very different regions in the brain with strikingly different effects. This suggests that there are multiple regions and pathways in the brain that have the potential to improve cognitive performance at old age."