Fight Aging! Newsletter, April 1st 2019

Today, Biogen and Eisai announced they would terminate the Phase 3 ENGAGE and EMERGE trials of aducanumab for early Alzheimer's disease. A futility analysis run by an independent data-monitoring committee concluded that that trials would not reach their primary endpoint, the slowing of cognitive decline as measured by the Clinical Dementia Rating (CDR-SB). Aducanumab is a monoclonal antibody that helps clear amyloid-β (Aβ) from the brain. The trials had recruited more than 3,200 patients around the world.

"This tells us that removal of amyloid in people with disease is too late. Amyloid is a disease trigger. Once the neurodegenerative disease process is up and running, it is up and running. Even though this trial was in the early symptomatic phase of AD, it is still in the phase when Aβ is no longer likely to be the driving process but where tau and inflammation probably are. I think Aβ is still a good target for the primary and maybe secondary prevention trials of AD, before tau and inflammation have started driving the disease. I think this solidifies the opinion that amyloid-targeted therapies do not have a clinical effect at the symptomatic stages of the disease process. Might anti-amyloid therapies work prior to the development of symptoms? Maybe, but with no symptomatic signal, it is risky to continue in that space. We clearly need other targets, and tau is the leading candidate for now."

The brain has been a black box for drug developers, but focusing on beta amyloid has long been viewed as the best hope for treating the mysterious ailment that affects millions of Americans and their families. For many, the hypothesis became an article of faith, motivating billions of in research spending and putting thousands of patients through clinical trials. "It's not science anymore. It has turned into a religion."

Biogen and Eisai will discontinue two late-stage trials designed to evaluate the efficacy and safety of the drug, aducanumab, which has cost the partners more than 830 million over the past three years. The results showed that the drug was unlikely to help patients, the companies said in a statement, and the discontinuation wasn't related to safety concerns. The latest failure, following the unraveling of similar experimental beta amyloid drugs from Merck & Co., Eli Lilly & Co., and Pfizer Inc. in large-scale trials, has scientists questioning whether the persistent focus on targeting the compound has prevented work on testing drugs against other possible Alzheimer's targets. Even so, researchers had thought that perhaps the Biogen compound might be different from previous failures.

Inflammation and dysfunction of fat tissue cause some of the insulin resistance in obese people. In many cases, that dysfunction is caused by senescent cells that already have been shown to be responsible for conditions related to aging and illness, including osteoporosis, muscle weakness, nerve degeneration, and heart disease. These cells also accumulate in the fat tissues of obese and diabetic people and mice.

In this study, the researchers, using genetically modified mice and wild-type (normal) mice, removed senescent cells two ways: by causing genetically-mediated cell death and by administering a combination of senolytic drugs. Senolytic drugs selectively kill senescent cells but not normal cells. The result: glucose levels and insulin sensitivity improved. The mice also showed a decline in inflammatory factors and a return to normal fat cell function. The senolytic drugs also prompted improved kidney and heart function, both of which are common complications of diabetes.

Cellular senescence is a cell fate that entails proliferative arrest and acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP). Although senescent cells exist in relatively small numbers in any particular tissue, they have been associated with multiple diseases of aging and are emerging as useful therapeutic targets for age-related diseases, including cardiovascular disease, pulmonary fibrosis, neurodegeneration, and osteoporosis. A number of stimuli, including potentially oncogenic, inflammatory, damage-related, and metabolic stimuli, can trigger a senescence response. Components of the SASP secreted by adipose-derived senescent cells have been postulated to confer insulin resistance upon metabolic tissues, inhibit adipogenesis, and attract immune cells that can exacerbate insulin resistance. Here, we determined whether removing senescent cells in the context of obesity improves metabolic phenotypes.

Recently, drugs that preferentially decrease senescent cell burden, termed senolytics, have been identified. We discovered the first senolytics based on our observation that senescent cells rely on several survival pathways to confer resistance to their pro-apoptotic SASP and intracellular cell damage signals. Knowing this, we identified dasatinib (D) and quercetin (Q) as orally bioactive drugs that transiently target these survival pathways to induce apoptosis preferentially in senescent cells.

We employed the combination of D plus Q (D + Q) in our studies for the following reasons. (a) In our hands, no senolytic investigated thus far targets all types of senescent cells. For example, unlike navitoclax (ABT263), fisetin, A1331852, A1155463, or Q on its own, D selectively targets senescent adipose progenitors, a key cell type for adipose tissue and metabolic function. (b) On the other hand, Q, unlike D, is effective against senescent endothelial cells, a cell type implicated in vascular complications of diabetes. (c) D + Q is effective in alleviating multiple age- and senescence-associated disorders, including many that are frequent complications or comorbidities of diabetes in preclinical animal models.

Here, we show that reducing senescent cell burden in obese mice, either by activating drug-inducible "suicide" genes driven by the p16Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra-abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity-related metabolic dysfunction and its complications.

This study represents the first clinical experience with AG10 in the target patient population of transthyretin amyloidosis cardiomyopathy (ATTR-CM). Administration of AG10 was well tolerated and was not associated with safety signals of potential clinical concern. In the present study AG10 treatment increased serum TTR levels from baseline and brought those levels to within the normal range in all subjects, both mutant and wild-type. This included subjects whose baseline levels were markedly below the normal range. The 28-day treatment duration of the present study limits any assessment of clinical benefit.

The serum level of transthyretin, long recognized both as a sensitive index of overall nutritional status and as an acute phase reactant, is becoming more widely appreciated as an independent predictor of survival in ATTR-CM. In one recent study of patients with wild-type ATTR-CM, regression analysis suggested that a 1 mg/dL decrement in serum transthyretin level is associated with a 7-11% decrement in survival.

Patients with an established diagnosis of ATTR-CM and NYHA Class II-III symptoms aged 18-90 years were eligible for the study. Subjects were randomized in a 1:1:1 ratio to AG10, 400mg or 800mg, or matching placebo, administered twice daily. The primary objective of the study was to evaluate the safety and tolerability of AG10 compared to placebo. Secondary endpoints included pharmacokinetics (AG10 plasma concentrations), change from baseline in serum transthyretin concentration, and two distinct ex vivo measures of transthyretin stabilization. The study enrolled 49 subjects, of which 14 (29%) had known mutant ATTR-CM. Subjects ranged in age from 60-86 years, with a mean of 74.1 years, and 92% were male. All subjects had symptomatic, chronic heart failure due to ATTR-CM with NYHA Class II or III symptoms. Importantly, on average subjects had relatively low transthyretin at baseline.

AG10 plasma concentrations were determined at peak following the initial dose, and at peak and trough on Days 14 and 28 of the study. Subjects in the placebo group experienced a mean reduction of 7±15% in serum transthyretin concentration by Day 28 relative to baseline. Conversely, subjects administered either 400mg or 800mg AG10 bid showed a dose-dependent, mean increase in circulating transthyretin of 36±21% and 50±38%, respectively. There was a greater treatment effect observed in AG10-treated subjects with mutant ATTR-CM (67±42%) as compared to subjects with wild-type ATTR-CM (33±20%). This might be explained in part by the lower serum transthyretin levels in mutant ATTR-CM subjects measured at baseline.

With advancing age, lean mass and bone mineral density decrease, while total fat mass increases and changes its distribution, particularly in the abdominal region, often without concomitant changes in body mass index (BMI). In mammals, fat mass accumulates as adipose tissue or ectopic lipid deposition. Adipose tissue is a dynamic organ involved in the regulation of energy homeostasis, mainly divided in three types, brown (BAT), white (WAT), and BEIGE which differ in embryogenesis, anatomy, and function. While BAT possesses high levels of mitochondria and is specialized in fat burning to generate heat, WAT is characterized by a low density of mitochondria and it is generally involved in lipid storage in two biological distinct compartments: subcutaneous (SAT) and visceral (VAT) adipose tissue. WAT is not only involved in the storage of lipids, but also plays an important role as immuno-endocrine organ.

With advancing age, BAT mass declines, while WAT increases reaching the maximum peak by early old age and changing its distribution toward a higher proportion of VAT. WAT redistribution is also accompanied by an accumulation of fat mass in non-adipose tissues and organs, such as muscle, liver, heart, pancreas and others, that normally contain only small amounts of fat, stored within lipid droplets (LDs). Adipose tissue shows also an extraordinary plasticity, in fact it can differentiate into another type of adipose tissue, such as BEIGE or replace the parenchyma of organs that undergo involution with age, such as the thymus.

The maintenance of a balanced amount of fat mass is crucial for health and survival. According to the "thrifty phenotype" theory, humans were selected to accumulate fat depots to face periods of food shortage. However, while a critical lower threshold of fat content exists, an upper threshold is apparently missing, and adipose tissue can accumulate in great amounts. The absence of an upper threshold for fat accumulation is probably due to the fact that this phenomenon did not occur in the wild frequently enough to undergo selection, or, alternatively, resulted neutral for the fitness of individuals.

With aging, the "thrifty phenotype" seems to emerge more dramatically, and the balance is tilted toward an increase of fat mass, at the level of VAT and SAT as well as in ectopic sites (liver, muscles, etc.). This increase in fat deposition at the level of SAT and VAT can be considered an adaptive response to modified health conditions interacting with contingent environmental conditions, leading eventually to decreased energy expenditure. However, in some cases the storage of surplus energy can not be claimed as the reason for fat accumulation, especially when this occurs ectopically at the expenses of other tissue types with important vital functions, as in the case of thymic involution or skeletal muscle infiltration.

In this case, it seems that fat deposition in the form of WAT is a sort of physiological program (genetically determined?) for organs and tissues undergoing age-related atrophy or involution. Different stem cell subpopulations such as muscle fibro-adipogenic progenitors and bone marrow mesenchymal stem cells preferentially differentiate to adipocyte with age, therefore, we are tempted to speculate that the pathway leading to this cell type is a sort of a default choice in involution processes. Should this speculation be verified, the reasons for this choice remain elusive.

The accumulation of WAT has been for long time viewed as detrimental, being the source of pro-inflammatory mediators and other important endocrine modulators and strongly associated with metabolic diseases such as insulin resistance and type II diabetes, cardiovascular diseases, and cancer. However, it is not totally clear whether this negative role is present also in extreme old age. Actually, data on body composition in nonagenarians and centenarians are largely missing, even though the BMI of these people is usually lower than that of younger (70-80 years-old) persons. It is possible that, as for other risk factors like lipid serum profile and inflammatory parameters, also the presence of a consistent amount of WAT can be important for survival at very advanced age. Further studies are needed to verify this hypothesis.

Exercise, nutritional changes, organelle dysfunction, and stress induce the systemic release of muscle-derived factors: cytokines (myokines) and metabolites (myometabolites) that exert autocrine, paracrine, or endocrine effects. Indeed, exercise preserves and ameliorates mitochondrial function and muscle metabolism, thereby affecting the release of myokines and metabolites, which might systemically counteract organ deterioration. In contrast, dysfunctional muscles can influence disease progression in other tissues.

The fibroblast growth factor 21 (FGF21) is a secreting myokine that can also be released in the bloodstream by other organs such as liver, heart, white adipose tissue (WAT), and brown adipose tissue (BAT). It is a starvation-like hormone with several metabolic functions aimed at overcoming nutrient deprivation by providing tissues with fuel. In skeletal muscle, FGF21 expression, in healthy conditions, is almost undetectable, and therefore, the circulating FGF21 is predominantly produced and released by the liver. In contrast, muscle-dependent systemic release of FGF21 increases with starvation, endoplasmic reticulum stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging. Moreover, FGF21 is a stress-induced myokine that has been proposed as a specific serum biomarker of muscle-specific mitochondrial disorders.

We and others recently demonstrated that in a muscle-specific OPA1 knockout animal model, characterized by mitochondrial dysfunction and by extensive muscle loss, the contribution of skeletal muscle to circulating FGF21 was predominant. In this model, FGF21 secreted from muscles mediates an integrated stress response that caused several systemic cell non-autonomous effects such as inflammation, metabolic alterations, and precocious senescence. Importantly, FGF21 deletion in OPA1 knockout muscles improved almost all systemic effects, while there was only a partial sparing of muscle mass. Injecting mice daily with exogenous FGF19, a closely related endocrine FGF member produced in the gut, increased skeletal muscle mass and strength. Remarkably, the skeletal muscle hypertrophy effects were not elicited by administrating FGF21. Thus, whether FGF21 is beneficial or detrimental for human health is still not clear, in part because the contribution of autocrine/paracrine-derived FGF21 signalling to muscle homeostasis has not been investigated yet.

In this study, muscle-specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21-dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy.

We show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting-induced muscle atrophy and weakness. The mass of isolated muscles from control-fasted mice was reduced by 15-25% compared with fed control mice. FGF21-null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control-fasted muscles, together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15%. Bnip3 inhibition protected against FGF21-dependent muscle wasting in adult animals.

In summary, the current study elucidates by using gain and loss of function approaches, a novel role for FGF21 in the control of skeletal muscle mass through the regulation of the anabolic/catabolic balance. These findings are important for the understanding of the molecular pathways that control muscle mass. Moreover, this study also open several new avenues for future investigation to define the mechanisms mediated by FGF21 in the interplay between muscle and other tissues such as bones, heart, and WAT in whole body homeostasis.

Age is a key risk factor for cognitive performance. Cognitive decline is common in older ages but recently there has been interest in understanding the age at which significant decline in cognitive abilities begins. Such knowledge has implications for the design of behavioral or pharmacological interventions since they are more likely to work if they are applied when, or even years before, individuals first begin to experience decline. Efforts to date are often based on cross-sectional studies which may be confounded by 'cohort effects'. Longitudinal studies suggest evidence of cognitive decline in middle age but that age trajectories differ by sex and cognition domain or task.

Longitudinal data that span many decades generally report minimal cognitive decline before the age of 65, but such studies are rare and also subject to limitations including small sample size, selection attrition, and retest or practice effects. Researchers examined cognitive decline among ~2,500 participants aged 25 to 95 years at recruitment in the Midlife in the United States (MIDUS) study, and all cognitive domains measured showed significant but small declines over 9 years, with differences in the timing and extent of change. The largest analysis to-date included a 10 year follow-up of ~7,400 participants aged 45-70 at recruitment of the Whitehall Study. The design of this study allowed for cross-sectional and longitudinal analysis. For the former analysis, performance on several tests were progressively lower with older age categories. In longitudinal analyses, there was some evidence of greater decline at older ages and of a linear trend in decline with increasing age for some of the tests, particularly in men.

UK Biobank is a large population cohort of adults who underwent medical, sociodemographic, mental health and cognitive assessment in 2006-2010 and are being followed up at intervals. The large age-distribution and follow-up enables cross-sectional as well as longitudinal analysis of age. In the current study of individuals aged 38 to 73 at baseline, we observed significantly lower performance on memory, attention, and processing tasks across successive age groups. Reasoning scores, based on the fluid intelligence test, were higher with successive age group until 60, then dropped to less than that of under 45 year olds. Longitudinal analysis of a subset of individuals with repeated measures of four tests showed linear declines in visual memory and processing speed tasks with age but of a much lesser degree than those observed in cross-sectional analyses. Decline rates in reasoning and prospective memory did not significantly differ with age. Taken together, our findings suggest that decline in cognitive abilities before age 65 is evident but small, and that observed cross-sectional differences in cognition from middle to older adult years may be due largely to age cohort effects.

Age-related changes in the intervertebral discs are the predominant contributors to back pain, a common physical and functional impairment experienced by older persons. Cellular senescence, a process wherein cells undergo growth arrest and chronically secrete numerous inflammatory molecules and proteases, has been reported to cause decline in the health and function of multiple tissues with age. Although senescent cells have been reported to increase in intervertebral degeneration (IDD), it is not known whether they are causative in age-related IDD.

To examine the impact of senescent cells on age-associated IDD, we used p16-3MR transgenic mice, which enables the selective removal of p16Ink4a-positive senescent cells by the drug ganciclovir. Disc cellularity, aggrecan content and fragmentation alongside expression of inflammatory cytokine (IL-6) and matrix proteases (ADAMTS4 and MMP13) in discs of p16-3MR mice treated with ganciclovir and untreated controls were assessed. In aged mice, reducing the percent of senescent cells decreased disc aggrecan proteolytic degradation and increased overall proteoglycan matrix content along with improved histological disc features. Additionally, reduction of senescent cells lowered the levels of MMP13, which is purported to promote disc degenerative changes during aging.

The findings of this study suggest that systemic reduction in the number of senescent cells ameliorates multiple age-associated changes within the disc tissue. Cellular senescence could therefore serve as a therapeutic target to restore the health of disc tissue that deteriorates with age.

A researcher has suggested that the perception that days last longer in childhood can be blamed on the ever-slowing speed at which images are obtained and processed by the human brain as the body ages. This phenomenon is attributed to physical changes in the aging human body. As tangled webs of nerves and neurons mature, they grow in size and complexity, leading to longer paths for signals to traverse. As those paths then begin to age, they also degrade, giving more resistance to the flow of electrical signals. These phenomena cause the rate at which new mental images are acquired and processed to decrease with age. This is evidenced by how often the eyes of infants move compared to adults - because infants process images faster than adults, their eyes move more often, acquiring and integrating more information.

The end result is that, because older people are viewing fewer new images in the same amount of actual time, it seems to them as though time is passing more quickly. "The human mind senses time changing when the perceived images change. The present is different from the past because the mental viewing has changed, not because somebody's clock rings. Days seemed to last longer in your youth because the young mind receives more images during one day than the same mind in old age."

People keep making new brain cells throughout their lives (at least until the age of 97), according to a study on human brains. The idea has been fiercely debated, and it used to be thought we were born with all the brain cells we will ever have. The researchers also showed that the number of new brain cells tailed off with age. And it falls dramatically in the early stages of Alzheimer's disease - giving new ideas for treating the dementia.

Most of our neurons - brain cells that send electrical signals - are indeed in place by the time we are born. Studies on other mammals have found new brains cells forming later in life, but the extent of "neurogenesis" in the human brain is still a source of debate. The study looked at the brains of 58 deceased people who were aged between 43 and 97. The focus was on the hippocampus - a part of the brain involved in memory and emotion.

Neurons do not emerge in the brain fully formed, but have to go through a process of growing and maturing. The researchers were able to spot immature or "new" neurons in the brains that they examined. In healthy brains there was a "slight decrease" in the amount of this neurogenesis with age. "I believe we would be generating new neurons as long as we need to learn new things. And that occurs during every single second of our life."

But there was a different story in the brains from Alzheimer's patients. The number of new neurons forming fell from 30,000 per millimetre to 20,000 per millimetre in people at the beginning of Alzheimer's. "That's a 30% reduction in the very first stage of the disease. It's very surprising for us, it's even before the accumulation of amyloid beta, a hallmark of Alzheimer's, and probably before symptoms, it's very early. Larger studies will need to confirm these findings and explore whether they could pave the way for an early test to flag those most at risk of the disease."

Until the new millennium, the adult heart was considered a postmitotic organ, but several recent studies have supported the notion that it possesses a population of endogenous cardiac stem/progenitor cells (CSCs) supporting myocardial cell turnover and regeneration due to their intrinsic potential to differentiate in all cardiac cell lineages. This discovery opened a new era for myocardial regeneration where endogenous cardiac stem/progenitor cells were introduced as direct regenerative agents and/or endogenous targets of regenerative therapy to effectively replenish the heart muscle cells, lost by injury and/or age, in order to improve/normalize myocardial function.

However, the pathological and pathophysiological cardiomyopathy that occurs with age also affects the stem cell microenvironment modifying adult stem cell biology and then their ability, during lifespan, to repair damaged tissues and organs. Accordingly, as shown for other stem cell types, cardiac stem cell (CSC) potential has also been found to be compromised or even lost with aging as a consequence of the accumulation and activation of senescence factors affecting myocardial homeostasis, producing DNA damage, and alteration of the telomere-telomerase system eventually leading to a senescent phenotype of CSCs. Despite this evidence, interesting studies have demonstrated that the old decompensated heart appears to maintain a functionally competent pool of CSCs during life and that the senescent phenotype of CSCs may be therefore reverted using growth factors or cardioprotective molecules. This accumulating knowledge is fundamental for the prospects of CSCs as main agents for myocardial regeneration because the majority of the patients in need of such therapy are indeed aged subjects.

During the late adulthood, the heart maintains a functionally competent CSC compartment, but the aged cardiac phenotype produces an accumulation of senescent CSCs. Aging and cellular senescence are a major hindrance to the endogenous regenerative efficacy of CSCs. However, the persistence in aged decompensated hearts of a population of functionally competent CSCs with long telomeres generates the hypothesis that endogenous CSCs may be indeed rejuvenated to regain robust regenerative potential. This population of functional yet old CSCs lacks senescent markers, expresses telomerase and cycling proteins, such as Ki67, and displays the capacity to migrate to injured zones generating a healthy progeny of young CMs. Indeed, as demonstrated in old humans, a pool of CSCs seems to maintain a growth reserve and self-renewing potential in the cardiac tissue, critical variables for effective cardiac homeostasis and repair during aging.

It is expected that a better understanding of the metabolic pathways and molecular mechanisms active in adult stem cells in old tissues may be helpful to develop genetic approaches or drugs to preserve their stemness potential during aging and to manipulate their quiescence, self-renewal, and differentiation. Several strategies able to decrease ROS levels, to restore or increase telomerase activity and telomere length in order to delay the natural aging process of the entire organism, have been studied in the past decade.

The present available evidence shows that the mammalian, including the human, myocardium possesses an "aged" CSC phenotype and this affects CSC self-renewal ability, differentiation, and regenerative potential. Thus, CSCs are not immortal. They undergo cellular aging in response to a variety of physiological and pathological demands. We can envision the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. Indeed, if CSC aging is really a stochastic cell autonomous process, then the possibility to rejuvenate the endogenous CSC population by stimulating their growth and self-renewing could be concrete. On the other hand, CSC aging could be a cell cycle-dependent process, affecting all or most of the endogenous CSC population, with a consequent irreversible loss of CSC regenerative capacity with time. If the latter is correct, it is predictable that the loss of CSC regenerative capacity with time progression is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The determination of whether the aged phenotype of the CSCs is reversible or irreversible has importance for the future of myocardial regeneration.

Impaired vascular function as a result of aging occurs due to the coalition of environment, oxidative stress, and inflammation. These factors result in reduced nitric oxide (NO) bioavailability, causing a failure of the vasculature to dilate in response to increases in shear stress during hyperaemia. Furthermore, vascular structure is also compromised with age as wall stiffness increases, reducing flexibility. Therefore, vascular dysfunction promotes cardiovascular disease (CVD) risk and contributes both to a reduction in health span and overall life expectancy. Given this premise there is an increasingly important but unmet need for interventions which aim to reduce inflammation and oxidative stress, while developing an environment conducive to vascular function.

Modifiable lifestyle factors, such as increased physical activity (PA) and/or exercise have been advocated to reduce vascular impairment and restore NO dependent vasodilatation, even in apparently healthy older cohorts. Multiple lines of evidence, including both human and pre-clinical models demonstrate that those individuals who are regularly active enjoy superior vascular function, with lower levels of systemic inflammation and oxidative stress. Vascular function, or specifically endothelial function, is commonly assessed non-invasively using the flow mediated dilation (FMD) technique. As cardiovascular events can be independently predicted by endothelial compliance, FMD has emerged as a conventional method to determine vascular function.

We conducted a systematic review and meta-analysis of controlled studies examining flow mediated dilatation (FMD) of athletic older persons and otherwise healthy sedentary counterparts to (i) compare FMD as a determinant of endothelial function between athletes and sedentary individuals and, (ii) summarize the effect of exercise training on FMD in studies of sedentary aging persons. Studies were identified from systematic search of major electronic databases. Thirteen studies with age ranges from 62 to 75 years underwent quantitative pooling of data. The majority of study participants were male.

Older athletes had more favorable FMD compared with sedentary controls. There was no significant improvement in the vascular function of sedentary cohorts following a period of exercise training. However, there was a significant increase in artery baseline diameter from pre to post intervention. In addition, there was no significant difference in endothelial independent vasodilation between the trained and sedentary older adults, or from pre to post exercise intervention. In conclusion, long-term aerobic exercise appears to attenuate the decline in endothelial vascular function, a benefit which is maintained during chronological aging. However, currently there is not enough evidence to suggest that exercise interventions improve vascular function in previously sedentary healthy older adults.

The drug strategy, called targeted protein degradation, capitalizes on the cell's natural system for clearing unwanted or damaged proteins. These protein degraders take many forms, but the type that is heading for clinical trials this year is one that researchers have spent more than 20 years developing: proteolysis-targeting chimaeras, or PROTACs. Because they destroy rather than inhibit proteins, and can bind to them where other drugs can't, protein degraders could conceivably be used to go after targets that drug developers have long considered 'undruggable': cancer-fuelling villains such as the protein MYC, or the tau protein that tangles up in Alzheimer's disease.

In diagrams, PROTACs often look like dumb-bells. They are molecules made up of two binding ends connected by a thin tether. The action happens on the ends. One grabs on to the target protein, while the other latches on to a ubiquitin ligase - part of the cell's natural rubbish-disposal system that labels defective or damaged proteins by slapping a small protein called ubiquitin onto them. Ubiquitin tags act as sort of 'Please collect' stickers that instruct the cell's protein shredder, called the proteasome, to do its thing.

Proximity can count for a lot in biology, so by simply bringing together the ligase and the target protein, a PROTAC ensures that the target will get marked for destruction. Ligases are efficient and ubiquitin, as the name suggests, is plentiful, so a single PROTAC should be able to perform its catch-and-release function repeatedly throughout the cell, suggesting that only a small amount of such a drug is needed for potent activity.

The longevity gene klotho keeps memory keen, but how? New research raises the possibility that it might influence cognition through its signaling partners FGF23 and the fibroblast growth factor (FGF) receptor. Researchers recently reported that mice lacking FGF23 have memory problems similar to those seen in klotho knockouts. Meanwhile, another group reported that older people with high levels of FGF23 in their blood are at elevated risk of developing dementia. However, changes in circulating FGF23 levels are also known to impair kidney function. Kidney disease by itself can harm cognition, leaving it unclear if FGF23 acts directly in the brain or indirectly in the periphery.

Klotho levels dwindle with age, and drop off steeply with disease progression in mouse models of amyloidosis. Conversely, high levels of klotho boost cognitive performance in people, and memory in mice. Another recent study adds genetic evidence for klotho's protective effect in the brain. Researchers found that the klotho variant associated with high expression and longevity seemed to negate some effects of the ApoE4 allele. Among 82 people with this protective klotho variant, ApoE4 carriers accumulated no more brain amyloid than noncarriers. The mechanism is unclear.

Researchers have elucidated at least one signaling pathway through which klotho acts. Klotho spans the cell membrane, where it binds FGF receptors to form a pocket that captures extracellular FGF, triggering intracellular signaling. It is unknown what effect this has on the brain. In the kidney, the binding of klotho and FGF23 stimulates excretion of phosphate and vitamin D, hence functions in their homeostasis. FGF23 levels appear to be tightly regulated. Mice with too much of it develop the vitamin-D-deficient bone disease rickets. Those with too little accumulate mineral deposits throughout their bodies and age faster, as do klotho knockouts.

Were the learning defects of the FGF23 knockout mice due to FGF23 in the brain? Probably not. The authors searched intensively for FGF23 mRNA or protein in wild-type mouse brain, but were unable to find significant expression. Because of this, they believe that brain klotho acts via other mechanisms, independent of FGF23. The FGF23 knockouts develop kidney disease, grow slowly, and die by 9 weeks of age. Kidney problems are linked to cognitive deficits. In particular, high FGF23 levels predict progression of kidney disease and worse cognition. Researchers believe the take-home message from these studies is the importance of kidney function for cognition.

Some common observations have been used to generate theories of ageing. The rate of living theory of ageing proposes to explain the variation in mammalian lifespans, it states that lifespan and metabolic rate are inversely correlated. Another theory is the mitochondrial free radical theory of ageing, this states that animals with high basal metabolic rates will generate greater levels of reactive oxygen species (ROS) and due to their detrimental effect, have shorter lifespans. Observed mammalian biology mostly aligns with these theories however there are a few notable exceptions, including the naked mole rat and microbats, that live much longer than their small body size and high metabolic rates would predict.

Microbats are exceptionally long-lived considering their small body size and high metabolic rates. For instance, the maximum lifespan for the bat; Myotis lucifugus (weight ~8g) is 34 years. In comparison the maximum lifespan of a mouse (Mus musculus) (weight ~30g) is 4 years. Bats have been shown to expend double the amount of energy in comparison to non-flying eutherian mammals and yet they live on average three times longer than non-flying eutherian mammals. This raises the question; how do bats maintain such high metabolic rates without succumbing to accumulating damage over their lifespan?

Oxidative stress has been a key focus for the majority of studies investigating longevity in bats. Mitochondrial dysfunction is evident in ageing and age-related diseases. Mitochondrial DNA (mtDNA) is considered to be more susceptible to mutagenesis due to the close proximity of mtDNA to ROS and also the high number of direct repeat regions prone to deletions. Bat mtDNA was found to have a lower number of repeat regions compared with other mammals. Bats were found to produce half to one third of the amount of hydrogen peroxide per oxygen molecular consumed compared to both shrews and mice. Research thus far indicates that bats produce less ROS and may also be more resistant to oxidative stress.

In this study we compared the mitochondrial lipidome and proteome of whole brain and skeletal tissues from adult Pipistrelle bats (maximal lifespan 12 years) with parallel sample types prepared from young and middle-aged Mus musculus. We used proteomics and ultra-high-performance liquid chromatography coupled with high resolution mass spectrometry lipidomics, to interrogate mitochondrial fractions prepared from tissues. Fatty acid binding protein 3 (FABP3) was found at different levels in mouse and bat muscle mitochondria and its orthologues were investigated in Caenorhabditis elegans knock-downs for LBP 4, 5, and 6. In the bat, high levels of free fatty acids and N-acylethanolamine lipid species together with a significantly greater abundance of FABP3 in muscle were found. We show that decreased quantities of FABP3 orthologues are detrimental to mitochondrial health. The literature supports this as a mechanism associated with mitochondrial dysfunction across many tissues. Mechanisms to increase levels of FABP3 or fatty acids in the mitochondrial compartment may be of interest in supporting mitochondrial health through the lifespan.

Researchers have found that caloric restriction reduces levels of innate immunity by decreasing the activity of a regulatory protein called p38, triggering a chain reaction effect ending in a reduced immune response. Innate immunity is like the security guard of the body, keeping an eye out for any unwelcome bacteria or viruses. If the innate immune system spots something, it activates an acute immune response. We need some degree of both kinds of immunity to stay healthy, but an overactive innate immune system - which occurs more often as we age - means constant low-grade inflammation, which can lead to myriad health issues.

The research was conducted in the microscopic nematode worm C. elegans. The most fundamental genes and regulatory mechanisms found in these worms are typically simpler versions of those present in humans, making them a good model for studying human aging, genetics, and disease. Researchers analyzed the levels of proteins and actions of genetic pathways during periods of caloric restriction. They were able to zero in on a particular genetic pathway that was regulated by the p38 protein. They saw that when p38 was totally inactive, caloric restriction failed and had no impact on innate immunity. When it was active, but at lower levels than normal, it triggered the genetic pathways that turned down the innate immune response to an optimal level.

After making this discovery, the researchers were curious to know if the well-known longevity mechanism of reduced IGF1 signaling also acted on the immune system. For over 20 years, study after study in many different organisms have confirmed that lower levels of IGF1 signaling contributes to a longer lifespan. This is thought to be due to the activation of protective factors by a protein called FOXO (called DAF-16 in C. elegans). A reduction in the activity of the FOXO-like gene seems to tell the worms that they are in a fasting-like state, and that nutrients may be scarce. This directs the worms to conserve energy, leading to a reduction in food intake. This self-imposed caloric restriction then leads to the lowering of the innate immune response.