It has been clear for a while that anti-amyloid antibodies can sweep plaque from the brain, but until now the question of whether this slows cognitive decline has remained hotly contended. Despite some positive signals from four such antibodies, the data have been messy and hard to interpret. At the a recent conference, researchers presented the cleanest data yet on this question. In a Phase 2 trial, the company's anti-amyloid antibody donanemab met its primary endpoint. Participants did not get better. Even so, donanemab slowed their decline by an average of 32 percent on a combined cognitive and functional measure.

Donanemab banished plaque from the brain in a majority of participants, while nudging down the rate of neurofibrillary tangle accumulation in the frontal cortex and other regions. The trial included several innovative elements, such as screening participants by tangle burden, using tau PET as a secondary outcome measure, and stopping dosing once amyloid was gone. Most Alzheimer's researchers welcomed the findings. At the same time, researchers emphasized that, as with other anti-amyloid immunotherapies, the cognitive benefit was small. "The donanemab story is the most encouraging news on the amyloid front, ever, but whether the effect size is clinically meaningful is questionable."

Donanemab is unique among Alzheimer's disease (AD) immunotherapies in that it targets a modified version of amyloid-β (Aβ) that has a pyroglutamate attached to the N terminus. This pathological form of Aβ is highly prone to aggregate, depositing in the core of all amyloid plaques, but is found nowhere else in the brain. In Phase 1 trials, donanemab busted up plaques fast, in many cases clearing all deposits within six months. However, even dramatic amyloid clearance has not translated into a clear cognitive benefit in past Phase 2 and 3 immunotherapy trials.

Given that donanemab completely cleared plaque, the researchers acknowledged that a 32 percent slowing may represent the most it can achieve in people at this stage of AD. "This is probably the ceiling for an amyloid-lowering drug." To do more for patients, researchers likely will have to treat earlier in a prevention paradigm, or combine anti-amyloid treatment with an anti-tau drug, he suggested.

We wondered what Dr Peyer's views were on classifying aging itself as a disease? "I have a somewhat controversial view on this amongst folks in our field," says Dr Peyer. "I believe that the entire discussion about whether aging should be considered a disease is actually little more than a distraction from the real, more technical issues standing in the way of getting a medicine that enhances healthspan from being approved for that use. Many of my colleagues advocate in good faith that this would be a key inflection point for the field, and I used to believe the same. However, the more I have come to understand about the way that these drugs would be regulated in the future, the less concerned that I am with worrying about categorizing aging as a disease."

"I do absolutely think that it is appropriate and proper to classify the build-up of damage that accumulates during aging as a disease. There is already a gray area about when other conditions are labeled a pathology vs not a pathology. We have categorizations for pre-diabetes, mild cognitive impairment, benign tumors, and high cholesterol. Are these conditions diseases? I would argue that it's not important what we call it. What is important is the following: (A) Can we run a clinical trial to address the condition and (B) would health insurance companies provide such a medicine to its patients?"

"One of the most valuable learnings from the pioneering work of Nir Barzilai on the TAME trial and other conversations with the FDA has been that building a composite chronic disease endpoint is already acceptable to the FDA. Building a drug that reduces stroke and heart disease risk (what the statins were approved for) has been acceptable to the FDA for ~20 years. Building a drug that reduces heart disease, stroke, Alzheimer's, cancer, and diabetes risk is also acceptable. What would change in this context if the regulators labeled aging a disease? Nothing. We just have to do the trial to show that such a drug is actually working. The path is already there for us. The real challenge is how we design and power these trials and whether we can use biomarker-based endpoints to make the iteration time of testing these medicines shorter."

A pilot human clinical trial in eight older adults 70 to 80 years of age reveals that supplementation with GlyNAC - a combination of glycine and N-acetylcysteine as precursors of the natural antioxidant glutathione - could improve many age-associated defects in older humans to improve muscle strength and cognition, and promote healthy aging. The study participants taking GlyNAC for 24 weeks saw improvements in many characteristic defects of aging, including glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, body fat, genomic toxicity, muscle strength, gait speed, exercise capacity, and cognitive function. The benefits declined after stopping supplementation for 12 weeks. GlyNAC supplementation was well tolerated during the study period.

As mitochondria generate energy, they produce waste products such as free radicals. These highly reactive molecules can damage cells, membranes, lipids, proteins, and DNA. Cells depend on antioxidants, such as glutathione, the most abundant antioxidant in our cells, to neutralize these toxic free radicals. Failing to neutralize free radicals leads to harmful and damaging oxidative stress that can affect mitochondrial function. Interestingly, glutathione levels in older people are much lower than those in younger people, and the levels of oxidative stress are much higher. Animal studies have shown that restoring glutathione levels by providing GlyNAC reverses glutathione deficiency, reduces oxidative stress, and fully restores mitochondrial function in aged mice.

Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel-oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improves naturally-occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance.

This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition. A 36-week open-label clinical trial was conducted in eight OAs and eight young adults (YAs). OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks.

GlyNAC supplementation for 24 weeks in OA corrected red blood cell GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks.

Naked mole-rats (NMRs; Heterocephalus glaber) are known for their exceptional longevity and remarkable resistance to cancer; indeed, only two cases of cancer reported in captive NMRs were reported after multi-year observation of large colonies. In addition, NMRs are strictly subterranean mammals that live in low-oxygen environments; therefore, they exhibit marked resistance to hypoxia. Interestingly, NMRs can survive in oxygen-deprived (anoxia) conditions for 18 min without noticeable injury. Despite accumulating considerable levels of oxidative damage and protein carbonylation under anoxic conditions, NMRs appear to be resilient to oxidative stress and mitochondrial injury, which is strikingly accompanied by a slower aging rate and increased longevity. In addition, NMRs display negligible senescence accompanied by high fecundity, and most importantly, remain healthy and are resistant to age-related diseases.

These attributes mean that the NMR has been utilized increasingly as an animal model for human aging and cancer research. Several cancer-resistant models have been described in this species. For example, NMR fibroblasts exhibit extreme sensitivity to contact inhibition in tissue culture, which is a potential anticancer mechanism regulated by INK4. An additional study demonstrated that hyaluronan, a high molecular mass polysaccharide of the extracellular matrix, triggers early contact inhibition. Furthermore, treatment with a combination of oncoproteins that trigger tumor formation in mouse cells does not cause malignant transformation of NMR cells, corroborating evidence suggesting that the NMR is resistant to both spontaneous cancer development and experimentally-induced tumorigenesis. Furthermore, it was reported that NMR-derived induced pluripotent stem cells are also tumor resistant.

To identify the mechanisms of longevity and cancer resistance in NMRs, we conducted comparative analyses of oncogenic signaling between NMR skin/lung fibroblasts (NSFs/NLFs), mouse skin fibroblasts (MSFs), and NIH 3T3 cells. We found that NMR cells showed altered Wnt/β-catenin signaling. Basal β-catenin expression was significantly higher in NMR cells than in mouse cells. In addition, β-catenin knockdown in NSFs induced senescence-like phenotypic changes. Meanwhile, we observed abundant lipid droplets with high levels of cholesterol in NMR cells. Because both β-catenin knockdown and cholesterol synthesis inhibition abolished lipid droplet formation and promoted senescence-like phenotypes, we investigated the functional link between β-catenin signaling, cholesterol metabolism, and cellular senescence.

These findings confirmed that NMR cells are intrinsically susceptible to cellular senescence, potentially due to their low rate of basal metabolism, which could be beneficial for longevity and cancer resistance. Hence, upregulation of the unique β-catenin pathway in NMR cells could counterbalance its strong senescence potential, thereby promoting longevity and survival under harsh conditions at the whole-organism level. Further analyses of the molecular mechanisms underlying the anti-senescence functions of cholesterol may reveal unique approaches to treating aging-related conditions.

Humans are born with tens of thousands of hematopoietic stem cells (HSCs) that collectively ensure lifelong production of blood and immune cells that protect us from infections. HSCs can either duplicate to produce more stem cell progeny or differentiate to produce distinct immune cell lineages, an extremely critical decision that ensures that the body achieves the fine balance between having enough immune cells to fight invaders while still retaining enough HSCs to maintain future blood production. As we age, HSCs accumulate mutations that lead to the emergence of genetically distinct subpopulations. This common phenomenon known as clonal hematopoiesis (CH) is known to start in early fifties and is frequently associated with loss of function mutations in the DNMT3A gene. CH is associated with a significantly higher risk of blood cancers, cardiovascular disease, stroke, and all-cause mortality.

"Previously, we showed that chronic infection significantly impairs the ability of wild-type HSCs to remain in a quiescent stem cell state. Prolonged (lasting several months) exposure to a systemic bacterial infection promoted an extensive differentiation of HSCs. While this produced sufficient immune cells to fight the infection, it also reduced the number of bone marrow HSCs by 90%. In contrast, HSCs in mice lacking Dnmt3a gene did not differentiate much. In fact, they underwent self-renewal to produce more HSCs. We undertook the current study to test our prediction that defective differentiation and increased duplication of Dnmt3a HSCs allows them to overtake and outcompete normal HSCs when fighting chronic infections or facing long-term inflammatory conditions."

Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovascular disease, and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between the acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We tested whether infection provides a selective pressure favoring the expansion of Dnmt3a mutant hematopoietic stem cells (HSCs) in mouse chimeras.

We created Dnmt3a-mosaic mice by transplanting Dnmt3a-/- and wild type (WT) HSCs into WT mice and observed the substantial expansion of Dnmt3a-/- HSCs during chronic mycobacterial infection. Injection of recombinant IFNγ alone was sufficient to phenocopy CH by Dnmt3a-/- HSCs upon infection. Transcriptional and epigenetic profiling and functional studies indicate reduced differentiation associated with widespread methylation alterations, and reduced secondary stress-induced apoptosis accounts for Dnmt3a-/- clonal expansion during infection. DNMT3A mutant human HSCs similarly exhibit defective IFNγ-induced differentiation. We thus demonstrate that IFNγ signaling induced during chronic infection can drive DNMT3A-loss-of-function CH.

Many elderly people suffer simultaneously from several, frequently very different diseases, a condition also known as multimorbidity. In a recent study, researchers have now identified a number of metabolic processes that are associated not only with one, but simultaneously with up to 14 diseases.

The scientists first examined the concentration of hundreds of different molecules in the blood samples of a total of 11,000 study participants. They then examined how the concentration of individual metabolites was related to the onset of a total of 27 serious diseases in the participants. The metabolites included not only known metabolic products such as sugars, fats, and vitamins, but also substances whose concentration depends on genetic or environmental factors. For example, the scientists were able to detect the degradation products of medications, coffee consumption or the presence of gut bacteria using a process known as molecular profiling.

The blood samples had already been taken from the participants more than 20 years ago and been stored at minus 196 degrees Celsius since then. At that time, the people were mostly healthy. The diseases they developed afterwards were systematically recorded in detail for more than 20 years through electronic hospital data.

For example, the team found that the concentration of many metabolites in the blood that were associated with disease onset were explained by impaired liver and kidney function, obesity, or chronic inflammation. But they also discovered that certain lifestyle factors or a reduced diversity of intestinal bacteria, also known as the gut microbiome, influence blood levels and can thus provide clues to the development of diseases over time. It turned out that half of all detected molecules were associated with an increased or decreased risk of at least one disease - the majority with multiple, sometimes very different, diseases, pointing to metabolic pathways that increase the risk of multimorbidity.

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity that is directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs.

Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression.

Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly it has emerged recently that non-proliferating neuronal cells present in the brain or cultivated in vitro can also exhibit some hallmarks, including SASP, typical for senescent cells that ceased to divide.

It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.

As many as one-fifth of people age 65 and older have some level of mild cognitive impairment (MCI) - slight changes to the brain that affect memory, decision-making, or reasoning skills. In many cases, MCI progresses to dementia, including Alzheimer's disease. Scientists have previously shown that lower-than-usual levels of blood flow to the brain, and stiffer blood vessels leading to the brain, are associated with MCI and dementia. Studies have also suggested that regular aerobic exercise may help improve cognition and memory in healthy older adults. However, scientists have not established whether there is a direct link between exercise, stiffer blood vessels, and brain blood flow.

Researchers followed 70 men and women aged 55 to 80 who had been diagnosed with MCI. Participants underwent cognitive exams, fitness tests, and brain magnetic resonance imaging (MRI) scans. Then they were randomly assigned to either follow a moderate aerobic exercise program or a stretching program for one year. The exercise program involved three to five exercise sessions a week, each with 30-40 minutes of moderate exercise such as a brisk walk. In both programs, exercise physiologists supervised participants for the first four to six weeks, then had the patients record their exercises and wear a heart rate monitor during exercise.

Forty-eight study participants - 29 in the stretching group and 19 in the aerobic exercise group - completed the full year of training and returned for follow-up tests. Among them, those who performed aerobic exercise showed decreased stiffness of blood vessels in their neck and increased overall blood flow to the brain. The more their oxygen consumption (one marker of aerobic fitness) increased, the greater the changes to the blood vessel stiffness and brain blood flow. Changes in these measurements were not found among people who followed the stretching program.

The microtubule-binding protein tau is a key player in Alzheimer's disease (AD) and frontotemporal dementia. The accumulation and aggregation of tau in the brain correlate with synaptic loss, neuronal loss, and cognitive decline. In patients with frontotemporal dementia, mutations in the tau gene, MAPT, lead to tau aggregation and cause widespread neurodegeneration. In addition to the neurotoxicity exerted by aggregated tau, soluble oligomeric forms of tau appear to be especially synaptotoxic.

Mice engineered to lack expression of MAPT have been shown to be protected against β-amyloid (Aβ)-induced synaptotoxicity, as well as against stress-induced and seizure-induced neuronal damage, and against learning and memory deficits resulting from traumatic brain injury. Moreover, reducing transgenic tau expression, even after tau has accumulated in mouse models of tauopathy, reverses the pathological effects of tau. These findings support the idea that the reduction of tau protein could be used as a therapeutic approach in AD or other tauopathies.

Translation of the neuroprotective effect of tau repression into a therapeutic approach for neurodegenerative diseases requires a treatment that reduces endogenous tau in the adult brain. We created a way to generate efficient, specific, and long-lasting down-regulation of the expression of endogenous tau by using a single viral administration: AAV encoding engineered zinc finger protein (ZFP) arrays that precisely target a short region of the genomic mouse MAPT sequence and down-regulate MAPT gene expression.

Using different AAV serotypes, we were able to reduce tau locally in the hippocampus - a brain region that is specifically affected by tau pathology in neurodegenerative diseases - through intracranial injections of AAV9 or brain-wide through intravenous delivery of blood-brain barrier-crossing AAV-PHP.B. In both cases, a single AAV administration was sufficient to repress tau mRNA and all isoforms of the protein by 50 to 80% in the brain and for as long as we carried out the study - nearly 1 year - following the treatment.

Furthermore, we performed proof-of-principle experiments for the use of tau-targeted ZFP-TFs to treat neurodegeneration in a mouse model in vivo: The repression of endogenous tau appeared to protect neurons from toxicity in mice with AD-like Aβ pathology (APP/PS1 mice). Tau repression by ZFP-TFs reduced amyloid plaque-associated neuritic dystrophies, which are a tau-dependent pathological hallmark in these mice.

Researchers have developed technology that can "retrain" skin cells to help repair damaged brain tissue. The nonviral tissue nanotransfection (TNT) technique effectively reprograms the skin cells to become vascular cells, which generate new blood vessels to help get blood to the damaged tissue. In tests, stroke-affected mice that received intracranial injections of the cells recovered nearly all of their motor function, and exhibited repair to damaged brain areas.

The newly reported approach uses TNT to introduce a key set of genes into skin cells, which then drive direct reprogramming of the cells into vascular cells. For their mouse studies, the team pre-conditioned the cells by introducing a cocktail containing the developmental transcription factor genes Etv2, Foxc2, and Fli1 (collectively, EFF) and injected the cells back into the stroke-affected brains, where they triggered the formation of new blood vessels to deliver blood supply to the tissue and help to repair damage.

The team's experiments found that mice given this cell therapy regained 90% of their motor function, with MRI scans showing that damaged areas of the brain were repaired within a few weeks. "MRI and behavioral tests revealed ~70% infarct resolution and up to ~90% motor recovery for mice treated with EFF-nanotransfected fibroblasts. Our results indicate that intracranial delivery of fibroblasts nanotransfected with the EFF cocktail leads to dose-dependent increases in perfusion, reduced stroke volume, and significant recovery of locomotive abilities in stroke-affected mice. We found that the mice have a higher recovery because the cells that are being injected into the affected area also release healing signals in the form of vesicles that help in the recovery of damaged brain tissue."

Atherosclerosis (AS) is a complex vascular disease that seriously harms the health of the elderly. It is closely related to endothelial cell aging, but the role of senescent cells in atherogenesis remains unclear. Studies have shown that peroxisome proliferator-activated receptor alpha (PPARα) inhibits the development of AS by regulating lipid metabolism. Our previous research showed that PPARα was involved in regulating the repair of damaged vascular endothelial cells. Detecting senescent cells in atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice, we found that PPARα delayed atherosclerotic plaque formation by inhibiting vascular endothelial cell senescence, which was achieved by regulating the expression of growth differentiation factor 11 (GDF11).

We demonstrated a likely causal role for PPARα in vascular endothelial cell senescence and occurrence of AS, where PPARα inhibited cell aging and plaque formation by directly targeting GDF11. Pharmacologic stimulation of PPARα alleviated atherosclerotic plaque formation, vascular endothelial cell damage, and senescence, as well as increasing GDF11 expression in Apoe-/- model mice. At the same time, we proved that PPARα directly targeted the aging-related protein GDF11, thereby affecting the aging, proliferation, apoptosis, and angiogenesis of vascular endothelial cells in vitro. Our findings are consistent with the general hypothesis that inhibiting the aging of vascular endothelial cells helps prevent the formation of atherosclerotic plaques. Our work suggests that targeting PPARα or senescent vascular endothelial cells could be a promising avenue for delaying, preventing, alleviating, or treating AS.

Type 2 diabetes occurs when insulin becomes less efficient at removing glucose from the bloodstream, resulting in high blood sugar that can cause abnormal cholesterol levels. A similar situation occurs in Alzheimer's disease, but rather than affecting the body as a whole, the effects are localized in the brain. When cholesterol rises, due to insulin resistance or other factors, the body starts a process known as reverse cholestrol transport, during which specific molecules carry excess cholesterol to the liver to be excreted.

Apolipoprotein E (APOE) is one of the proteins involved in reverse cholesterol transport. APOE is also the strongest risk factor gene for Alzheimer's disease and related dementia, and an independent risk factor for Type 2 diabetes and cardiovascular disease. Similarly, reduced activity of another cholesterol transporter, ATP-binding cassette transporter A1 (ABCA1), correlates with increased risk of cardiovascular disease, Type 2 diabetes, and Alzheimer's disease. "While most people are aware of so-called 'good cholesterol (HDL),' and 'bad cholesterol (LDL),' associated with risk of heart attack and stroke, these broad concepts are also applicable to a healthy brain. Moving cholesterol to where it is needed in the body has positive effects on many physiological processes and can help clear misfolded proteins that accumulate in the brain."

Increasing the activity of ABCA1 is expected to positively influence insulin signaling and reduce inflammation in the brain, making it a potential therapy for both Type 2 diabetes and Alzheimer's disease. In this study, the research team designed a way to identify small molecules that improve the function of ABCA1 in the body while avoiding unwanted effects to the liver. The researchers honed in on a specific small molecule, CL2-57, due to its ability to stimulate ABCA1 activity with positive effects on liver and plasma triglycerides. The use of this compound showed improved glucose tolerance and insulin sensitivity, as well as reduced weight gain, among other beneficial effects.

The hallmarks of aging are remarkably similar across mammals, but the rate vastly differs and the molecular basis for this natural variation in longevity is not well understood. This suggests that studying the aging process in exceptionally long-lived species, such as bats, will enable us to elucidate the mechanisms underlying naturally evolved longer healthspans and ultimately contribute to a greater understanding of aging biology. Relative to body mass, bats show the longest lifespans of all mammals and exhibit little signs of senescence. For this reason, bats are now being recognised as novel, relevant models to study the mechanisms of healthy aging.

Comparative studies focused on bats have furthered our understanding of variation in aging across the mammal tree of life and suggested factors that may underlie their extended healthspans: telomeres, mitochondria, microbiome, and metabolome. A recently published longitudinal study highlighted that bats exhibit a unique, age-related gene expression pattern associated with DNA repair, immunity, and autophagy. Indeed, autophagy and proteostasis were previously suggested to be the common mechanisms that maintain health in long-lived species, including bats. Enhanced autophagy has also been suggested as an anti-viral mechanism in bats which may also contribute to longer healthspans. However until now, studying the age-dependent changes of autophagy in wild bat populations has been hindered by the logistical challenges

Autophagy is a convergent mechanism of multiple longevity pathways, playing a role in lifespan extension promoted by reduced insulin/IGF-1, mTOR inhibition, and dietary restriction in mammals. Functional studies in model species demonstrate that reduced autophagy shortens lifespan, while increased autophagy extends it. Accordingly, many studies have demonstrated that autophagy decreases with age, and it has been inferred that this gradual decrease could play a major role in the functional deterioration of aging organisms.

Here, drawing on more than eight years of mark-recapture field studies, we report the first longitudinal analysis of autophagy regulation in bats. Mining of published population level aging blood transcriptomes (M. myotis, mouse and human) highlighted a unique increase of autophagy related transcripts with age in bats, but not in other mammals. This bat-specific increase in autophagy transcripts was recapitulated by the western blot determination of the autophagy marker, LC3II/I ratio, in skin primary fibroblasts (M. myotis, Pipistrellus kuhlii, mouse), that also showed an increase with age in both bat species. Further phylogenomic selection pressure analyses across eutherian mammals (n=70 taxa; 274 genes) uncovered 10 autophagy-associated genes under selective pressure in bat lineages. These molecular adaptations potentially mediate the exceptional age-related increase of autophagy signalling in bats, which may contribute to their longer healthspans.

New clinical and experimental studies indicate epidemiological and neuropathological links connecting ischemic brain neurodegeneration with the genotype and phenotype of Alzheimer's disease. Human investigations have revealed that Alzheimer's disease is a risk factor for stroke and vice versa, indicating that the same or closely related pathological mechanisms may be involved in the development of both disorders. Animal studies have also presented a synergistic link between brain ischemia and Alzheimer's disease, leading to an increased risk of cognitive decline and development of Alzheimer's disease-type dementia.

The main cause of ischemic stroke in humans is atherosclerosis. Atherosclerosis is also associated with Alzheimer's disease. At least 33% cases of Alzheimer's disease have neuropathological changes resulting from small vessel arteriosclerosis. Atherosclerosis has been found to coexist with cerebral amyloid angiopathy and it also correlates well with cognitive decline. On the other hand, the increased level of amyloid in the post-ischemic brain causes the accumulation of amyloid not only in the brain tissue, but also in the vessel wall, causing the development of cerebral amyloid angiopathy.

Reduction in the length of cerebral vessels post-ischemia or impaired cerebral blood flow in the brain as a result of vasoconstriction and/or the development of cerebral amyloid angiopathy not only limits the transport of energy substrates and the supply of oxygen and nutrients to the brain through the blood-brain barrier after ischemia, but also reduces the clearance of potential neurotoxins from the brain, such as amyloid. This leads to the idea that brain vascular diseases, such as ischemic brain episode, may make the regions in the brain more susceptible to Alzheimer's disease pathology, due to impaired clearance of amyloid from the brain and dysfunctional tau protein. Alternatively, post-ischemic brain neurodegeneration and Alzheimer's disease may finally represent independent but convergent common pathological mechanisms, and can therefore be expected to have common proteomic and genomic risk factors.

Aging is an irreversible process and the primary risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD). Mitochondrial impairment is a process that generates oxidative damage and ATP deficit; both factors are important in the memory decline showed during normal aging and AD. Tau is a microtubule-associated protein, with a strong influence on both the morphology and physiology of neurons. In AD, tau protein undergoes post-translational modifications, which could play a relevant role in the onset and progression of this disease. Also, these abnormal forms of tau could be present during the physiological aging that could be related to memory impairment present during this stage.

We previously showed that tau ablation improves mitochondrial function and cognitive abilities in young wild-type mice. However, the possible contribution of tau during aging that could predispose to the development of AD is unclear. Here, we show that tau deletion prevents cognitive impairment and improves mitochondrial function during normal aging as indicated by a reduction in oxidative damage and increased ATP production. Notably, we observed a decrease in cyclophilin-D (CypD) levels in aged tau-/- mice, resulting in increased calcium buffering and reduced mitochondrial permeability transition pore (mPTP) opening.

The mPTP is a mitochondrial structure whose opening is dependent on CypD expression, and new evidence suggests that this could play an essential role in the neurodegenerative process during AD. In contrast, hippocampal CypD overexpression in aged tau-/- mice impairs mitochondrial function evidenced by an ATP deficit, increased mPTP opening, and memory loss; all effects were observed in the AD pathology. Our results indicate that the absence of tau prevents age-associated cognitive impairment by maintaining mitochondrial function and reducing mPTP opening through a CypD-dependent mechanism. These findings are novel and represent an important advance in the study of how tau contributes to the cognitive and mitochondrial failure present during aging and AD in the brain.