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- The Relentless Focus on Amyloid Clearance for Later Stage Alzheimer's Disease is Disintegrating
- Senescent Cells Cause a Sizable Fraction of the Consequences of Type 2 Diabetes
- Phase II Clinical Trial Results for the Eidos Therapeutics Approach to Transthyretin Amyloidosis
- Why Does the Aging Metabolism Bias Towards Fat Accumulation and Lipid Deposition?
- FGF21 and Muscle Function
- Decline in Cognitive Function is Small Prior to Age 65
- Senescent Cells as a Contributing Cause of Degenerative Disc Disease
- Proposing Physical, Neurological Explanations for Age-Related Differences in the Perception of the Passage of Time
- New Evidence for Adult Neurogenesis to Occur Even in Late Old Age in Humans
- On Adult Cardiac Stem Cells and their Aging
- Long-Term Aerobic Exercise Slows Age-Related Decline in Vascular Function
- Hijacking the Proteasome to Dispose of Unwanted Molecules in Age-Related Disease
- Does Klotho Act on Cognitive Function via FGF23?
- Comparing the Mitochondria of Mice and Long-Lived Bats
- Calorie Restriction Acts via p38 to Reduce Inflammation due to Innate Immune Activity
The Relentless Focus on Amyloid Clearance for Later Stage Alzheimer's Disease is Disintegrating
In hindsight, the Alzheimer's research and development community of the past fifteen years or so has been a strange place. The vast, overwhelming majority of funding has gone towards attempts to clear amyloid-β in later stage Alzheimer's disease, largely via immunotherapies. This strategy has failed, over and again, long past the point at which it was defensible to blame that failure on the challenging nature of the underlying projects to first make immunotherapies work at all, and then to make them work in the brain. Large-scale funding was spent on repeated attempts to clear amyloid-β even as the research community was settling on the consensus that aggregation of amyloid-β is a feature of early Alzheimer's. It only causes mild cognitive impairment on its own, but sets the stage for the later accumulation of hyperphosphorylated tau. It is tau aggregates and their surrounding biochemistry that cause the real harm, the severe dysfunction and death of neurons.
Where years of relentless failure did not move the leaders who determined strategy for Alzheimer's development at the large scale, the rise of plausible, much cheaper alternatives has finally produced motion. Large anti-amyloid programs are being cancelled, trial development halted. It is becoming apparent that low cost senolytics have a large effect on late stage Alzheimer's disease animal models, perhaps more so than many of the immunotherapies when they were tested in mice. Meanwhile, groups are working on drainage or filtration of cerebrospinal fluid, which should clear out a usefully large fraction of all of the protein aggregates involved in neurodegeneration, again much more cheaply than immunotherapies. Other researchers are focused on removing bacterial and viral contributions to amyloid buildup and neuroinflammation.
Ironically, just as this flourishing of alternative and potentially more cost effective development programs takes place, some of the anti-amyloid immunotherapies are finally starting to achieve their goals, to remove significant amounts of amyloid-β from the human brain. Yet they haven't moved the needle on patient outcomes. This upheaval, when taken as a whole, seems a positive development. The old industry is being disrupted by the growth of a new industry. Bad allocation of capital is being cleared out, and more productive new allocations of capital are being made. The Alzheimer's research community of the early 2020s will be a much more diverse ecosystem with a greater expectation of success.
Biogen/Eisai Halt Phase 3 Aducanumab Trials
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."
Alzheimer's Drug Failure Leaves Scientists Seeking New Direction
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.
Senescent Cells Cause a Sizable Fraction of the Consequences of Type 2 Diabetes
For the overwhelming majority of patients, type 2 diabetes is a self-inflicted condition. It is the consequence of excess visceral fat tissue, accumulated and held over the years. This type of fat is metabolically active and distorts the operation of metabolism in ways that accelerate the progression of many aspects of aging and age-related disease. Even quite late in the progression of the condition, patients can effectively turn back type 2 diabetes and its consequences via the use of a sustained low calorie diet and consequent weight loss. That more people do not do this is quite eye-opening, given that the alternative is unpleasant medications, side-effects, and the continuation of the disease process leading to an early death.
One of the primary ways in which visceral fat causes harm is via increased levels of chronic inflammation. Inflammation is a necessary part of the immune response to pathogens and injury, provided it lasts a short time only. But when it runs continually, it produces significant dysfunction in tissue maintenance and repair, and accelerates disease processes in all of the common age-related conditions. Visceral fat tissue can produce inflammation in numerous ways: because fat cells secrete signals similar to those of infected cells; fat cells tend to produce DNA debris that can provoke the immune system; and, relevant to research noted here, greater amounts of fat tissue encourage the creation of larger numbers of senescent cells.
The accumulation of lingering senescent cells in all tissues of the body is one of the fundamental causes of aging. Cells become senescent in large numbers constantly, day in and day out, largely resulting from somatic cells reaching the Hayflick limit on replication. Cells can also become senescent as the result of injury, DNA damage, a toxic environment, and the signals of other, nearby senescent cells. Near all senescent cells are quickly destroyed, either self-destructing via apoptosis, or removed by the immune system. It is the tiny fraction that evade this fate that contribute to aging. They largely achieve this end via a potent mix of secreted signals that spur chronic inflammation, destructive remodeling of the surrounding extracellular matrix, and altered behavior in normal cells. Wherever we see chronic inflammation in aging, we should be thinking of senescent cells.
Fortunately, senolytic therapies to selectively destroy senescent cells are presently under active development. New biotechnology companies and development programs are arriving in this part of the industry on a regular basis now, and a significant and growing amount of funding is now available for this work. Even better, a range of low-cost, easily obtained drugs and other compounds (such as the dasatinib and quercetin combination, fisetin, piperlongumine, and the FOXO4-DRI peptide) have been shown to remove a fair fraction of senescent cells in animal studies. Some are presently in initial human trials. Any older person suffering one or more of the many age-related conditions that appear likely to be actively maintained and driven by senescent cells, and who wishes to responsibly self-experiment with senolytics, can certainly do so with just a little knowledge and effort. These are interesting times.
Removal of 'zombie cells' alleviates causes of diabetes in obese mice
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.
Targeting senescent cells alleviates obesity-induced metabolic dysfunction
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.
Phase II Clinical Trial Results for the Eidos Therapeutics Approach to Transthyretin Amyloidosis
The protein transthyretin can misfold and form solid deposits of amyloid. This occurs to an increasing degree with age, and it is becoming clear that transthyretin amyloid contributes meaningfully to a range of age-related conditions, and is not only a problem in the small minority of individuals who rise to the level of being diagnosed with transthyretin amyloidosis. Many of those have a mutation in the transthyretin gene that predisposes them to the formation of amyloid, but again, the accumulation of this amyloid is one of the contributing causes of aging and age-related disease for all of us: osteoarthritis, heart failure, spinal stenosis, and more. Thus we should all be quite interested in progress towards the development of therapies.
Eidos Therapeutics is working on a fairly traditional approach to the treatment of transthyretin amyloidosis, a small molecule drug AG10 that must be taken continuously, and that alters the behavior of transthyretin to prevent the formation of amyloid. The company recently raised a sizable amount of funding to support their later stage clinical trials. This was accomplished prior to the publication of phase 2 trial results, but at a point in time at which the company had enough data for the principals to feel quite confident in progressing to much larger phase 3 trials. The paper I'll point out here outlines the results of the phase 2 trial, in which both people with age-related and genetic transthyretin amyloidosis were given AG10. It appears to improve short-term measures of the condition, though it remains to be seen as to whether this approach can actually reverse existing amyloid deposition to any degree, or the consequent pathology.
When it comes to the role of transthyretin in aging, I'm much more in favor of approaches that remove transthyretin amyloid, such as the catalytic antibodies under development at Covalent Biosciences, rather than approaches such as that pioneered by Eidos Therapeutics, in which only the progression of the condition is slowed or stopped. Reversal of the damage via a form of repair is a treatment that can be applied every so often, perhaps once every few years at most, rather than having to be continuously applied. Furthermore it can be applied at any stage of the condition to improve matters for the patient, and can be applied repeated for greater effect. A way of halting the creation of new transthyretin amyloid is only marginally helpful for someone who is greatly impacted by large amounts of the stuff clogging up his or her cardiovascular system.
Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy
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.
Why Does the Aging Metabolism Bias Towards Fat Accumulation and Lipid Deposition?
Irina Conboy's pithy description of what aging does to the operation of metabolism runs much as follows: "stem cells are sleeping, so damage is not regenerated. Instead you now make fibrous tissue, and deposit fat tissue to replace the damage. Then gradually over time, you just turn into this big scar and big fat blob." It is certainly the case that the older body seems to tend to hold on to lipids, create fat tissue, and put fats and other lipids into cells where they are usually not found in large amounts in youth. We might well ask why this happens. Is it the result of damage, some form of dysregulation of normal metabolism that is entirely harmful, or is it at least in part an evolved compensation that helps to attenuate some of the consequences of the underlying molecular damage that causes aging?
The authors of today's open access paper argue that both adaptive and maladaptive processes are in play. Nothing in biology is simple, and the observed redistribution of fat and changes in metabolism may be both harmful and protective when considered in various contexts, or when pieces of the whole are examined in isolation. That in later years it becomes challenging to maintain a good body weight, as the amount of work required to attain that goal ever increases, is no excuse for letting things slide, of course. While it may well be the case that some aspects of excess fat tissue are protective, the epidemiological evidence overwhelmingly demonstrates that, when taken as a whole, being even modestly overweight raises the risk of age-related disease, increases lifetime medical cost, increases mortality, and reduces life expectancy. Those negative effects scale up as the weight and excess fat tissue increase.
The Dual Role of the Pervasive "Fattish" Tissue Remodeling With Age
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.
FGF21 and Muscle Function
Fibroblast growth factor 21, FGF21, is one of many proteins to emerge as a target for further research during the past few decades of investigation into the biochemistry of calorie restriction. The practice of calorie restriction, reducing calorie intake by up to 40% while maintaining optimal micronutrient levels in the diet, has been found to reliably slow aging and extend life span in most of the species and lineages tested to date. The effect size is much larger in short-lived species than in long-lived species such as our own, unfortunately, and this is generally true of all interventions that upregulate beneficial stress responses. Calorie restriction spurs greater activity in cellular housekeeping processes such as autophagy, and otherwise makes cells more efficient and resilient. The outcome is a slowing of near all measures of aging.
Because calorie restriction produces sweeping changes in the operation of metabolism, it has been a slow and expensive process to determine the important controlling mechanisms, genes, and proteins. That process still continues today, but more of a focus is placed on well-known areas of study, those discovered some years ago. FGF21 and surrounding biochemistry is one such area - and a complicated area it is too. FGF21 levels increase with age, but also with calorie restriction, which clearly slows aging. Effects and processes relating to FGF21 seem different in obese individuals versus those of normal weight, and different again in aging.
So far it seems a bit of a mess, which probably means that any sort of therapy resulting from this research will have to be narrowly targeted to specific situations and specific tissues. An example of work that might be heading in that direction, eventually, is the role of FGF21 in muscle, as outlined in the open access paper noted below. FGF21 appears to control the reduction in muscle mass following inactivity and starvation, but is also involved in the beneficial cellular housekeeping process of mitophagy, necessary for effective muscle maintenance and function. So even here there are multiple processes to consider, and which appear to stand somewhat in opposition to one another.
Fibroblast growth factor 21 controls mitophagy and muscle mass
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.
Decline in Cognitive Function is Small Prior to Age 65
Researchers here process the enormous set of health data found in the UK Biobank to conclude that there is comparatively little sign of cognitive decline in cohorts younger than age 65. After that, loss of function sets in quite rapidly, however. This is good news for those of us taking good care of our health, and who have a long time yet before reaching 65. Not so great for the older contingent in the population, but we really don't need any more incentives than already exist in order to forge ahead with the development of rejuvenation therapies. Repair of the damage that causes aging, and aging of the brain in particular, is the only path forward likely to produce meaningful results in the clinic over the next ten to twenty years.
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.
Senescent Cells as a Contributing Cause of Degenerative Disc Disease
At this point, I suspect it will surprise no-one who follows the field to learn that the accumulation of senescent cells is a significant cause of degenerative disc disease. The evidence from a mouse study that is provided in the open access paper here doesn't quite rise to establishing that claim, but it is compelling nonetheless. Given the role of cellular senescence in arthritis, a disease of localized chronic inflammation, it is logical to also expect a role in the degeneration of intervertebral discs, as this is also a condition of aging in which inflammation seems important.
Senescent cells, even while present in only comparatively small numbers, generate a potent mix of molecules that spurs chronic inflammation and is destructive of surrounding tissue structure. Fortunately early senolytic compounds, those shown to destroy a sizable fraction of senescent cells cells in animal studies, are cheap and readily available to anyone willing to try this self-experiment. It is just a pity that so few older people know this at the present time - the hundreds of millions worldwide who are suffering when perhaps they need not be.
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.
Proposing Physical, Neurological Explanations for Age-Related Differences in the Perception of the Passage of Time
Why does the perception of the passage of time change with age? Having glanced through the short paper referenced in these publicity materials, it has the look of another of the many airy theories on the operation of the mind that must wait around for however long it takes for neuroscience to advance to the point of being able to say anything sensible about how perceived experience relates to physical structure and cellular biology. Still, one has to start somewhere. Final answers and understanding must be preceded by theories that prompt lines of investigation. That theorizing will start out entirely unsupported, and only incrementally become better and more scientific. We shouldn't be holding our collective breath waiting on those final answers, of course. They are quite the long way away.
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."
New Evidence for Adult Neurogenesis to Occur Even in Late Old Age in Humans
You might have missed it, but the past year has seen quite the debate in scientific circles over whether or not humans exhibit the same processes of neurogenesis in adult life that are observed in mice. Neurogenesis is the process by which new neurons are created in the brain and integrated into neural circuits. It is a part of the plasticity that allows for cognitive function and maintenance of that function in the face of damage. Obviously, this is a very important topic for those groups seeking ways to apply regenerative medicine to the brain.
Prior to the discovery of adult neurogenesis in the 1990s, it was thought that no such process took place after early development, and that the tissues of the adult brain were not maintained in this way. Since the 1990s an enormous amount of investigative work on this topic has taken place in mice, and comparatively little in human brains and brain tissue. In this context, much upheaval occurred in the wake of a study published last year that found no evidence of adult human neurogenesis. Shortly thereafter, another study was published with contradictory results, showing that there were signs of neurogenesis. The debate continues, and we will see more, ever more careful studies on this topic. Currently the weight of evidence leans in the direction of neurogenesis in adults, thankfully - if the process exists, then there is a path to enhance it in older individuals, in order to find ways to postpone and reverse portions of age-related neurodegeneration.
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."
On Adult Cardiac Stem Cells and their Aging
Does the adult mammalian heart contain a population of stem cells capable of tissue repair? If so, they are not very active; the heart is one of the least regenerative of organs, alongside the brain and the rest of the central nervous system. Opinions and study results differ on whether or not cardiac stem cells exist in any meaningful sense in the adult heart. If they do, there is the possibility of coercing them into greater efforts in tissue maintenance. This is possibly a faster path to regeneration of a damaged or aging heart than any of the other options. However, this would also require that these stem cells not only exist, but also survive into old age in a sizable enough population to produce regeneration. This is another area of study in which there are more questions than answers.
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.
Long-Term Aerobic Exercise Slows Age-Related Decline in Vascular Function
The study here measures vascular function in athletic and sedentary older individuals, finding that, as one might expect, long-term exercise produces a slower pace of decline in the ability of blood vessels to respond to circumstances by relaxing or contracting as needed. The molecular damage of aging impairs this function, and blood vessels stiffen, leading to rising blood pressure. Aerobic exercise slows the pace of many of the aspects of aging, this one included, though it doesn't appear to extend overall life span in mouse studies. Rather the period of life spent healthy is extended. Whether or not this holds up in humans is an interesting question; epidemiological studies show correlations between regular exercise and something like five years of additional life expectancy. People are not mice, and these two approaches to scientific discovery can't really be directly compared to one another, unfortunately.
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.
Hijacking the Proteasome to Dispose of Unwanted Molecules in Age-Related Disease
Cells are equipped with a protein disposal system in the form of the proteasome. Damaged or excess proteins are tagged with ubiquitin, and shuttled to the proteasome where they are dismantled into component parts that can be reused to build new proteins. The popular science article noted here discusses an approach to interfacing with this cellular maintenance system that is presently under developement, delivering carefully designed molecules that ensure a specific protein is tagged with ubiquitin, thus persuading the cell to destroy it. Over the course of aging, cells become exposed to any number of unwanted forms of molecular waste, many of which are proteins of one sort or another, and it is possible that finding ways to deliver those molecules to the proteasome could prove to be an effective therapy.
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.
Does Klotho Act on Cognitive Function via FGF23?
Klotho is a longevity gene in that more of the protein it codes for acts to modestly extend life in mice. Levels of klotho protein decline with age, and increased amounts appear to produce beneficial outcomes in health and longevity in part via stem cell function. Klotho also influences cognition, and a number of research groups are working on approaches, such as gene therapies to upregulate klotho expression, or delivery of recombinant protein fragments of the full klotho molecule, that might at some point result in ways to enhance cognitive function in humans, old and young alike.
Klotho is known to be closely related to FGF23, and research into this relationship has uncovered roles for klotho throughout the body, in many organs. This popular science article focuses on the brain however, covering research results suggesting that the influence of klotho on cognitive function might be quite circuitous and indirect, involving other organs in the body. This isn't an unreasonable suggestion - it is certainly the case in other, better known systems of regulation.
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.
Comparing the Mitochondria of Mice and Long-Lived Bats
Like naked mole-rats, bats are outliers among mammals when it comes to metabolism and longevity. They live much longer than similarly-sized mammals. We can hypothesize that the demands of living in oxygen-poor underground environments, in the case of naked mole-rats, and the demands of flight, in the case of bats, leads to a more resilient cellular biochemistry. That in turn has the side-effect of greater longevity. Much of the investigation of this hypothesis is focused on mitochondria, the power plants of the cell, and their differing composition between species. The membrane pacemaker view of aging suggests that species differences in life span among mammals arise in large part due to the degree of resistance to oxidation of cell membranes, particularly those of mitochondria. Mitochondrial function is critical to tissue function, and aging is associated with a growing malaise in mitochondria: poor quality control, rising levels of damage and dysfunction.
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.
Calorie Restriction Acts via p38 to Reduce Inflammation due to Innate Immune Activity
The practice of calorie restriction, reducing calorie intake by up to 40% while still obtaining optimal micronutrient intake, slows aging in most species tested to date. The effect on life span is much larger in short-lived species than in long-lived species, but the short-term health benefits are similar in mice and humans, even though mice live up to 40% longer when calorie restricted, and humans clearly do not. One component of the beneficial response to calorie restriction is a reduction in inflammation, particularly important given the prominent role that chronic inflammation plays in the aging process. In later life the immune system falls into an inflammatory, overly active, but ineffective state, a combination of the states known as inflammaging and immunosenescence. This disrupts tissue maintenance and accelerates the progression of all of the most common age-related diseases. Control over inflammation is a very desirable goal for older individuals.
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.