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  • Clearance of Senescent Cells Reverses the Peripheral Neuropathy Caused by Chemotherapy
  • Alpha-Ketoglutarate Supplementation Modestly Increases Life Span in Mice
  • SENS Research Foundation Issues 2020 Annual Report
  • Recent Studies on the Changing Gut Microbiome in Aging
  • Higher Temperature Slows Osteoporosis, an Effect Mediated by Polyamine Produced by Gut Microbes
  • Evidence for Familial Longevity to be Largely Cultural Rather than Genetic
  • Increased Insulin Receptor Expression Improves Memory in Old Rats
  • Upregulation of Unacetylated Ghrelin Slows Age-Related Muscle Loss in Mice
  • Using Direct Conversion of Cells to Investigate the Behavior of Aging Tissues
  • Targeting Inflammatory Microglia in the Treatment of Neurodegenerative Disease
  • The Aging of Macrophages Impairs Peripheral Nerve Regeneration
  • Lowered Body Temperature is Important in the Beneficial Calorie Restriction Response
  • Metformin Found to Reduce Liver Inflammation
  • Geroscience and Ovarian Aging
  • Long Term mTORC1 Inhibition Slows Muscle Aging in Mice via Preservation of Neuromuscular Junctions

Clearance of Senescent Cells Reverses the Peripheral Neuropathy Caused by Chemotherapy

A primary goal of chemotherapy is to force cancerous cells into programmed cell death or cellular senescence. Cellular senescence is a state of growth arrest that should normally be triggered by exactly the sort of damage and dysfunction exhibited by cancer cells, but cancer is characterized by a mutation-induced ability to bypass those restrictions. Chemotherapy remains the primary approach to cancer therapy, but chemotherapeutic agents are still at best only marginally discriminating. Treating cancer with chemotherapy has always been a fine balance between harming the cancer and harming the patient. Even in the best of outcomes, it is well established that chemotherapy causes lasting damage. There are many unpleasant, lingering side-effects, and in fact chemotherapy lowers remaining life expectancy significantly. It is about as bad as a smoking habit when it comes to its effects on later mortality.

With the growing understanding of the role of senescent cells in aging, it has become clear that much of the long-term harm that results from chemotherapy results from the greatly increased burden of senescent cells that it produces. This is obviously a better outcome than dying from cancer, but it is nonetheless a problem that should be addressed. Senescent cells secrete a potent mix of inflammatory signals known as the senescence-associated secretory phenotype. This is highly disruptive to tissue function when sustained over the long term, even given a comparatively small number of senescent cells in comparison to normal cells in a tissue. Cellular senescence directly contributes to near all of the common, ultimately fatal age-related conditions.

Fortunately, the research community is developing a variety of senolytic therapies: drugs, gene therapies, immunotherapies and others, all capable of selectively destroying senescent cells. These have proven able to reverse many aspects of aging and the progression of numerous age-related diseases in animal models, and are presently undergoing human trials. It seems clear that the first senolytic therapies should be capable of reversing many of the long-term consequences of chemotherapy as well, a point well illustrated by today’s open access paper.

Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice

Chemotherapy-induced peripheral neuropathy, a common dose-limiting toxicity of many chemotherapy regimens, limits the potentially curative effects of systemic chemotherapy. Particularly, platinum-based chemotherapeutics, such as cisplatin, are known to cause systemic neuronal toxicity. Clinically, cisplatin-induced peripheral neuropathy (CIPN) presents as burning, shooting or electric-shock-like pain affecting the feet and hands, for which no effective treatments or preventive measures are available.

An important senescence phenotype, termed therapy-induced senescence (TIS), can be induced by DNA damage-based chemotherapeutics. The genotoxic stress caused by these agents induces senescence during cancer treatment and has been shown to promote the adverse effects of chemotherapy. Cellular senescence, a conserved response to stress, results in a stable cell cycle arrest while maintaining cell viability and metabolic activity. The distinct metabolic and signaling features of senescent cells include a senescence-associated secretory phenotype (SASP). The expression of SASP includes the secretion of numerous molecules, including growth factors, proteases, cytokines, chemokines, and extracellular matrix components, which mediate the paracrine activities of senescent cells. Despite the relatively low proportion of senescent cells in tissues, the SASP allows these cells to generate durable local and systemic deleterious effects in most tissues, which contribute to the pathogenesis of a variety of diseases including chemotherapy toxicity.

We hypothesized that senescence and the SASP might also play a role in CIPN following neuronal DNA damage, and the depletion of senescent cells may be an effective treatment of peripheral neuropathy induced by cisplatin. We showed that cisplatin induces peripheral neuropathy, as confirmed by mechanical and thermal pain assessment, and was associated with the accumulation of senescent-like neuronal cells in the dorsal root ganglia (DRG) using immunostaining and qPCR for senescence biomarkers. Furthermore, we provided genetic and pharmacologic evidence that selective clearance of senescent-like DRG neurons alleviates CIPN.

To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological senolytic agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir to selectively kill senescent cells. We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following chemotherapeutic cancer treatment might be an effective therapy for the debilitating side effect of CIPN.

Alpha-Ketoglutarate Supplementation Modestly Increases Life Span in Mice

Alpha-ketoglutarate supplementation has been shown to modestly extend life span and improve measures of health in old mice; the publicity materials here accompany the formal release of that paper. Recently, a novel epigenetic clock was used to suggest that alpha-ketoglutarate supplementation in old humans can reduce epigenetic measures of aging, though since this was a novel epigenetic clock, those results should not yet be taken too seriously. Confirming studies are needed, assessing other metrics.

Alpha-ketoglutarate supplementation may act to produce benefits via reductions in excessive inflammatory signaling. Given the sizable influence that the chronic inflammation of aging has on the development of disease and dysfunction, any approach to achieve that goal should be at least in principle interesting. Effect size matters, of course, and here in mice it is both modest and gender-specific, usually signs that effects in humans will be small at best.

A metabolite produced by the body increases lifespan and dramatically compresses late-life morbidity in mice

Studies show that blood plasma levels of alpha-ketaglutarate (AKG) can drop up to 10-fold as we age. Fasting and exercise, already shown to promote longevity, increase the production of AKG. AKG is not found in the normal diet, making supplementation the only feasible way to restore its levels. AKG is involved in many fundamental physiological processes. It contributes to metabolism, providing energy for cellular processes. It helps stimulate collagen and protein synthesis and influences age-related processes including stem cell proliferation. AKG inhibits the breakdown of protein in muscles, making it a popular supplement among athletes. It also has been used to treat osteoporosis and kidney diseases.

Middle-aged mice that had AKG added to their chow were healthier as they aged and experienced a dramatically shorter time of disease and disability before they died. “The mice that were fed AKG showed a decrease in levels of systemic inflammatory cytokines. Treatment with AKG promoted the production of Interleukin 10 (IL-10) which has anti-inflammatory properties and helps maintain normal tissue homeostasis. Chronic inflammation is a huge driver of aging. We think suppression of inflammation could be the basis for the extension of lifespan and probably healthspan, and are looking forward to more follow up in this regard. We observed no significant adverse effects upon chronic administration of the metabolite, which is very important.”

Many of the study results were sex specific, with female mice generally faring better than males. Fur color and coat condition were dramatically improved in the treated females; the animals also saw improvement in gait and kyphosis, a curvature of the spine often seen in aging. The females also saw improvements in piloerection, which involves involuntary contraction of small muscles at the base of hair follicles. Male mice treated with AKG were better able to maintain muscle mass as they aged, had improvements in gait and grip strength, less kyphosis and exhibited fewer tumors and better eye health.

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms, can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes such as collagen synthesis and epigenetic changes. Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.

SENS Research Foundation Issues 2020 Annual Report

The SENS Research Foundation, like the Methuselah Foundation it emerged from, is one of the more important organizations involved in the creation and shaping of the present R&D communities focused on treating aging as a medical condition. In earlier days, advocates and philanthropic programs were attempting to sway the research community (and the world at large) into taking intervention in aging seriously at all. In other words to accept that the evidence was strongly in favor of the plausibility of rejuvenation therapies, that the evidence had been strongly in favor for a long time, and that the long-standing reluctance of researchers and developers to engage in this work was entirely irrational.

That battle was in essence won a decade ago, all over bar the shouting. The research community is now wholeheartedly in favor of the treatment of aging, albeit in a wide variety of ways, not all of which are likely to work. Now advocates and philanthropic programs focus on helping the best and most promising research programs to achieve meaningful progress: provision of funding at early stages, removing roadblocks such as a lack of tooling in the space, giving them the publicity they need, persuading researchers to work on better rather than worse approaches, and so forth.

The best and most promising programs are those that can in principle produce rejuvenation in old people, and the SENS Research Foundation approach to identifying such programs has always been that they must result in periodic repair of the forms of cell and tissue damage that lie at the root of aging. It remains the case that most researchers in the field are not working on potential rejuvenation technologies, but rather on ways to tinker with metabolism in late stage aging that might make it slightly more resilient to damage. Thus there remains a great deal of work to be undertaken by advocates and philanthropists, or indeed anyone who would like to see sizable gains in human longevity sooner rather than later.

SENS Research Foundation 2020 Annual Report (PDF)

At our 2013 conference at Queens College, Cambridge, I closed my talk by saying, “We should not rest until we make aging an absurdity.” We are now in a very different place. After a lot of patient explanation, publication of scientific results, conferences, and time, our community persuaded enough scientists of the feasibility of the damage repair approach to move SENS and SENS Research Foundation from the fringes of scientific respectability to the vanguard of a mainstream community of scientists developing medical therapies to tackle human aging.

Then we made the same case to investors and entrepreneurs; now, rejuvenation companies built on or inspired by our research are part of a robust ecosystem of basic science and biotech venture capitalists advancing the mission. After serving on the board for ten years, it was great to join the team full time last fall. While resources affect the pace of our progress, so do regulations and other government policies. So we began a lively dialogue with policymakers by inviting discussions of regulatory reform at our conferences and by hosting the Deputy Secretary of Health and Human Services, Eric Hargan, at our January health care event in San Francisco. More and more influential people consider aging an absurdity. Now we need to make it one.

Stepwise Visualization of Autophagy for Screening Remediation of Intraneuronal Aggregates

People often assume that an increase in autophagy automatically results in an increase in the ultimate degradation of unwanted molecular waste, but in fact the word only refers to the delivery process: it’s possible to have an increase in autophagy (or in markers of autophagy) that is ultimately futile. Typical methods of testing autophagy activity can fool investigators into thinking that the affected cells are engaged in robust and successful autophagy, when instead they are signs of futile autophagy and associated with cellular dysfunction. To sort out this confusion, determine what’s really being delivered to the lysosome, and pinpoint disruptions in the autophagy process, Dr. Andersen’s team team has been developing a system to visualize each of the key steps along the way.

Retrolytic Therapy to Destroy Cells with Reactivated “Jumping Genes”

With SRF sponsorship, Dr. Gudkov’s lab is developing a proof of concept for future rejuvenation biotechnologies that will ablate cells with active retrotransposon activity. For this initial demonstration, Gudkov will use a transgenic “suicide gene” system similar to the INK-ATTAC system that first demonstrated the rejuvenating effects of destroying senescent cells in aging mammals. In this case, the suicide gene system will be triggered by the activation of the interferon response to retroviral reactivation instead of a senescence-associated gene. Just as INK-ATTAC paved the way to the development of today’s senolytic therapies (drugs and other approaches that destroy senescent cells), this suicide gene system for the elimination of cells harboring reactivated retrotransposons holds the promise of paving the way for similarly-powerful future “retrolytic” therapies.

Functional Neuron Replacement to Rejuvenate the Neocortex

The maintenance of the brain against degenerative aging processes poses extreme challenges. Only recently have researchers succeeded in integrating new neurons into areas of the brain involved in cognitive functions. Surgically transplanting a small number of neuronal progenitors into a local brain structure has been done to date but cannot realistically scale to the sheer size of the brain, or keep up with the rate of age-related neuronal loss. Therefore, maintenance of the aging brain requires a system for ongoing dispersal of neuronal precursor cells across the brain. To accomplish this goal, SENS Research Foundation is supporting Dr. Jean Hébert’s innovative strategies to overcome these critical challenges. To enable the dispersal of replacement neurons noninvasively and throughout the brain, Dr. Hébert’s team will next take advantage of the unique properties of microglia, the specialized macrophage immune cells of the brain. Unlike neurons and their precursors, microglia are highly motile cells, able to disperse widely throughout the brain. Hébert’s strategy is to transplant microglia into the brains of mice and then reprogram the new microglia into cortical projection neurons after they disperse throughout the brain.

Engineering cyclodextrins for the Removal of Toxic Oxysterols as a Treatment For Atherosclerosis and other diseases of aging

Dr. O’Connor’s team has created a family of novel cyclodextrins that are able to selectively remove toxic forms of cholesterol from early foam cells and other cells in the blood, thus forming a potential treatment for atherosclerosis. In 2019, SENS Research Foundation announced the launch of Underdog Pharmaceuticals, Inc. (Underdog), a pharmaceutical company focused on the development of this program for disease-modifying treatments for atherosclerosis and other age-related diseases. Its co-founders are Matthew O’Connor, Ph.D., and Michael Kope, formerly the Vice President of Research and the founding Chief Executive Officer, respectively, of SRF. Mike and Oki have worked incredibly hard to transition a piece of SRF’s basic research to the next level, stepping into the private sector and creating a treatment for age-related disease based on one of SRF’s successful proof-of-concept programs. Ten or twenty years ago, cardiovascular disease research meant developing better stents or bypass techniques; Underdog aims to ensure that atherosclerosis won’t even exist in the future. All of us at SRF wish Mike and Oki success in this endeavor.

Targeting Secondary Senescence

Scientists have relatively recently discovered the phenomenon of secondary senescence. For reasons which we are only beginning to understand, existing senescent cells can cause other cells in the body to become senescent. Although this research is still in an early stage, it is beginning to appear that secondary senescent cells behave differently from primary senescent cells: they produce less SASP, but more fibrillar collagens – something that is normally suppressed in primary senescent cells. Granted their differences in origin and function, might secondary senescent cells also be differentially susceptible to senolytic therapies? For instance, might they be resistant to senolytic drugs that are effective against primary senescent cells, requiring a new generation of targeted “secondary senolytics” to eliminate – or might they be exceptionally susceptible to particular such treatments? SENS Research Foundation Forever Healthy Postdoctoral Fellow Tesfahun Admasu’s work seeks to find answers to these questions.

Target Prioritization of Tissue Crosslinking

One cause of stiffening in long-lived tissues is crosslinking, where one strand of structural protein becomes chemically bound to an adjacent strand, limiting the range of motion of both strands. Prior SRF-funded work in Dr. David Spiegel’s lab at Yale paved the way to the discovery of the therapeutic glucosepane-cleaving enzyme candidates that our startup company Revel Pharmaceuticals is now working to advance into functional rejuvenation biotechnologies. However, AGEs are not the only cause of crosslinking in aging tissues. The sheer number of a given type of crosslink is moreover not necessarily a good parameter for determining how we should prioritize that crosslink type as a rejuvenation target. Recognizing the importance of prioritizing our targets, SRF is funding a systematic study in “normally”-aging, nondiabetic mice by Dr. Jonathan Clark at the Babraham Institute in Cambridge. These mice are fed diets containing labeled amino acids, which are then incorporated into extracellular matrix proteins during synthesis. This allows Dr. Clark’s group to track the rate at which proteins are synthesized, crosslinked, and replaced over time.

Recent Studies on the Changing Gut Microbiome in Aging

Today’s research materials are a selection of recent studies on the gut microbiome and its relationship to the aging process. The scientific community has in recent years uncovered a great deal of new information regarding the way in which the gut microbiome both influences health and exhibits detrimental changes with age. Some of the microbes of the digestive tract are responsible for the generation of beneficial metabolites such as butyrate, indoles, and propionate. Unfortunately these populations decline in number with advancing age, and this negatively impacts tissue function throughout the body. Additionally, harmful inflammatory species increase in number. This contributes to the state of chronic inflammation that characterizes old age and accelerates the progression of all of the common age-related conditions.

The causes of age-related shifts in these microbial populations are not well understood, particular recently discovered changes that take place in earlier life. There is evidence for dietary changes to be involved, as well as the decline of the immune system’s ability to suppress harmful microbes, and the loss of integrity of intestinal barrier tissue. Which of these are more significant or less significant is an open question, however. It is also an open question as to how great an influence this has on long-term health and longevity; it wouldn’t be surprising to find it in the same ballpark as that of exercise.

This is an age-related change that is amenable to reversal in the near term. Animal studies show that fecal microbiota transplant from young animals to old animals resets the gut microbiome to a more youthful distribution of species, and results in improved health and extended life spans. This procedure is already carried out in human medicine for certain conditions, and could thus be expanded to other uses. Other potential approaches also exist, such as inoculation with bacterial proteins to encourage the immune systems to suppress harmful species, or sizable sustained dosage with a suitable mix of probiotics. We’ll likely see many such initiatives in the years ahead.

Relationship between Diet, Microbiota, and Healthy Aging

The gastrointestinal tract is colonized by a set of microorganisms that include not only bacteria but also viruses, fungi, and protozoa. Unlike other microorganisms, these are not identified as pathogens by our immune system, but rather coexist symbiotically with the enterocytes. So far, it is known that its composition contains a total of 52 different phyla and up to 35,000 different bacterial species, the large majority being Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria.

As we age, progressive changes are produced in the morphology and function of the microbiota – a decrease in Firmicutes and Bifidobacterium, with diversity in the patterns of abundance for Clostridium. The mechanism by which the microbiota changes with age is not yet fully understood. Lifestyle changes, and particularly diet, play an important role. As aging is often accompanied by a reduction in quantity and variety of aliments containing fiber, it often leads to a risk of malnourishment. This could alter its diversity and provoke inflammatory and metabolic disruption, causing inflammatory diseases in the intestine, such as irritable bowel, obesity, etc. Additionally, the microbiota can modulate changes in aging related to innate immunity, sarcopenia, and cognitive function, which are essential components of the frailty syndrome.

Gut Microbiome Composition is Associated with Age and Memory Performance in Pet Dogs

Gut microbiota can crucially influence behavior and neurodevelopment. Dogs show unique similarities to humans in their physiology and may naturally develop dementia-like cognitive decline. We assessed 29 pet dogs’ cognitive performance in a memory test and analyzed the bacterial 16S rRNA gene from fecal samples collected right after the behavioral tests. The major phyla identified in the dog microbiomes were Bacteroidetes, Firmicutes, and Fusobacteria, each represented by more than 20% of the total bacterial community. Fewer Fusobacteria were found in older dogs and better memory performance was associated with a lower proportion of Actinobacteria. Our preliminary findings support the existence of links between gut microbiota, age, and cognitive performance in pet dogs.

Gut microbes could unlock the secret to healthy ageing

The study included 422,417 unrelated individuals in the UK Biobank who had undergone genotyping to identify their genetic make-up. Information was also collected on a wide range of diseases and other characteristics including BMI and blood pressure. The average age of participants was 57 years and 54% were women. The researchers found that higher levels of eleven bacteria (estimated from genetic data) were associated with a total of 28 health and disease outcomes. These included chronic obstructive pulmonary disease (COPD), atopy (a genetic tendency to develop allergic diseases like asthma and eczema), frequency of alcohol intake, high blood pressure, high blood lipids, and BMI. To take one example, higher levels of the genus Ruminococcus were linked with increased risk of high blood pressure.

Higher Temperature Slows Osteoporosis, an Effect Mediated by Polyamine Produced by Gut Microbes

Osteoporosis is the name given to the characteristic age-related loss of bone mass and strength. The extracellular matrix of bone tissue is constantly remodeled, created by osteoblasts and broken down by osteoclasts. The proximate cause of osteoporosis is a tilt in the balance of these processes, favoring osteoclast activity and thus slow loss of bone structure.

Today’s research materials discuss a most intriguing result: in mice, maintaining a higher environmental temperature slows the progression of osteoporosis. Interesting, but is it a path to therapy? As is always the case when looking at metabolic responses to environmental differences in mice, there is the question of whether similar effects in humans are anywhere near as large All too many examples of this sort of thing are, unfortunately, clearly of little interest as a basis for human therapies because larger mammals respond less strongly. Here, however, a range of epidemiological data from hotter versus colder regions of the world suggests that, yes, the effect of temperature on osteoporosis in humans may be large enough to care about.

Perhaps the most interesting part of this work is the investigation into underlying mechanisms. It appears that the effect of temperature on osteoporosis is mediated by differences in the gut microbiome. In hotter climates, there is a greater microbial production of the metabolite polyamine, known to beneficially affect bone tissue maintenance. Transplanting gut microbes from high temperature environment mice to mice with osteoporosis modestly reverses the progression of the condition, improving bone density, but this benefit is not realized in mice in which polyamine production is inhibited.

Stronger bones thanks to heat and microbiota

Many biologists are familiar with Allen’s Rule, according to which animals living in warm areas have a larger surface area in relation to their volume than animals living in colder environment. Indeed, a larger skin surface allows better evacuation of body heat. By placing several groups of adult mice in a warm environment, scientists observed that while bone size remained unchanged, bone strength and density were largely improved.

What about human beings? The research team analysed global epidemiological data on the incidence of osteoporosis in relation to the average temperature, latitude, calcium consumption, and vitamin D levels. Interestingly, they found that the higher the temperature, the fewer hip fractures – one of the main consequences of osteoporosis – regardless of other factors.

Scientists wanted to understand the role of the gut microbiome in these metabolic modifications. To this end, they transplanted the microbiota of mice living in a 34°C environment to osteoporotic mice, whose bone quality was rapidly improved. Thanks to the state-of-the-art metagenomic tools developed in their laboratory, the scientists then succeeded in understanding the role played by microbiota. When adapts to heat, it leads to a disruption in the synthesis and degradation of polyamines, molecules that are involved in ageing, and in particular in bone health.

Warmth Prevents Bone Loss Through the Gut Microbiota

Osteoporosis is the most prevalent metabolic bone disease, characterized by low bone mass and microarchitectural deterioration. Here, we show that warmth exposure (34°C) protects against ovariectomy-induced bone loss by increasing trabecular bone volume, connectivity density, and thickness, leading to improved biomechanical bone strength in adult female, as well as in young male mice. Transplantation of the warm-adapted microbiota phenocopies the warmth-induced bone effects. Both warmth and warm microbiota transplantation revert the ovariectomy-induced transcriptomics changes of the tibia and increase periosteal bone formation.

Combinatorial metagenomics / metabolomics analysis shows that warmth enhances bacterial polyamine biosynthesis, resulting in higher total polyamine levels in vivo. Spermine and spermidine supplementation increases bone strength, while inhibiting polyamine biosynthesis in vivo limits the beneficial warmth effects on the bone. Our data suggest warmth exposure as a potential treatment option for osteoporosis while providing a mechanistic framework for its benefits in bone disease.

Evidence for Familial Longevity to be Largely Cultural Rather than Genetic

It is certainly possible that a small number of people have mutations or genetic variants that confer notable longevity. The small lineage exhibiting a PAI-1 loss of function mutation springs to mind as an example of this sort of thing. But for the overwhelming majority of long-lived lineages, the evidence on genetic contributions to longevity tends to support the hypothesis that familial longevity arises much more from lifestyle and environment than from inherited genetics. The data from very large genetic databases points to genetic variants contributing little to variation in human life span. The data on exercise, diet, and environmental factors such as particulate air pollution and persistent viral infection regularly results in larger effect sizes for late life mortality.

The familial resemblance in length of adult life is very modest. Studies of parent-offspring and twins suggest that exceptional health and survival have a stronger genetic component than lifespan generally. To shed light on the underlying mechanisms, we collected information on Danish long-lived siblings (born 1886-1938) from 659 families, their 5379 offspring (born 1917-1982), and 10,398 grandchildren (born 1950-2010) and matched background population controls through the Danish 1916 Census, the Civil Registration System, the National Patient Register, and the Register of Causes of Death.

Comparison with the background, population revealed consistently lower occurrence of almost all disease groups and causes of death in the offspring and the grandchildren. The expected incidence of hospitalization for mental and behavioral disorders was reduced by half in the offspring (hazard ratio 0.53) and by one-third in the grandchildren (0.69), while the numbers for tobacco-related cancer were 0.60 and 0.71, respectively. Within-family analyses showed a general, as opposed to specific, lowering of disease risk. Early parenthood and divorce were markedly less frequent in the longevity-enriched families, while economic and educational differences were small to moderate.

The longevity-enriched families in this study have a general health advantage spanning three generations. Having a long-lived parent or grandparent who had at least one long-lived sibling is associated with a substantial health and survival advantage in our study. Most notable is the strength of the associations, and that these are found for a wide range of diseases and causes of death, suggesting a fundamentally slower aging in these families and not just avoidance of specific diseases.

The combination of a particularly low incidence of mental and behavioral disorders and tobacco-related cancers combined with demographic characteristics such as low occurrence of teenage parenthood and early marriage and divorce implicate behavior as a key mechanism underlying the three-generation health and survival advantage observed. We found no evidence that the associations were driven by socioeconomic advantages in the longevity-enriched families either in the 1916 census or in the civil registration system over the last half-century.

Increased Insulin Receptor Expression Improves Memory in Old Rats

This is a interesting example of modulating the metabolism of the aging brain in order to improve its function, without any attempt to address the underlying cell and tissue damage that causes loss of function. Researchers delivered recombinant insulin receptor protein to the hippocampus of old rats, and demonstrated improved memory function as an outcome of this intervention. An age-related decline in insulin metabolism has been implicated in neurodegenerative conditions, but it is somewhat hard to pick this apart from reduced blood flow, blood-brain barrier dysfunction, and other related issues that contribute to the declining function of the brain. Hence this effort to attempt to modify insulin metabolism somewhat distinctly from other mechanisms.

As demonstrated by increased hippocampal insulin receptor density following learning in animal models and decreased insulin signaling, receptor density, and memory decline in aging and Alzheimer’s disease, numerous studies have emphasized the importance of insulin in learning and memory processes. This has been further supported by work showing that intranasal delivery of insulin can enhance insulin receptor signaling, alter cerebral blood flow, and improve memory recall. Additionally, inhibition of insulin receptor function or expression using molecular techniques has been associated with reduced learning.

Here, we sought a different approach to increase insulin receptor activity without the need for administering the ligand. A constitutively active, modified human insulin receptor (IRβ) was delivered to the hippocampus of young (2 months) and aged (18 months) male Fischer 344 rats in vivo. The impact of increasing hippocampal insulin receptor expression was investigated using several outcome measures, including Morris water maze and ambulatory gait performance, immunofluorescence, immunohistochemistry, and Western immunoblotting.

In aged animals, the IRβ construct was associated with enhanced performance on the Morris water maze task, suggesting that this receptor was able to improve memory recall. Additionally, in both age-groups, a reduced stride length was noted in IRβ-treated animals along with elevated hippocampal insulin receptor levels. These results provide new insights into the potential impact of increasing neuronal insulin signaling in the hippocampus of aged animals and support the efficacy of molecularly elevating insulin receptor activity in vivo in the absence of the ligand to directly study this process.

Upregulation of Unacetylated Ghrelin Slows Age-Related Muscle Loss in Mice

Ghrelin is best known for its role in the mechanisms of hunger, but it has two different forms, only one of which induces hunger. Both forms are known to affect muscle tissue metabolism, and this may be one of the ways in which calorie restriction slows the onset of muscle loss with age, a condition known as sarcopenia. Researchers here increase levels of the non-hunger-inducing ghrelin in mice and show that this does indeed slow the onset and progression of sarcopenia, and thus might be a basis for therapy.

Sarcopenia, the decline in muscle mass and functionality during aging, might arise from age-associated endocrine dysfunction. Indeed, muscle wasting follows the general decline in trophic hormones and the establishment of a chronic mild inflammatory status characteristic of aging. Ghrelin is a gastric hormone peptide circulating in both acylated (AG) and unacylated (UnAG) forms that have anti-atrophic activity on skeletal muscle. AG is the endogenous ligand of the growth hormone secretagogue receptor (GHSR-1a), and it is involved in metabolic regulation and energetic balance through induction of appetite, food intake, and adiposity. UnAG does not induce GH release and has no direct effects on food intake, but it shares with AG several biological activities on cell types lacking AG receptor.

In particular, both AG and UnAG have direct biological activities on skeletal muscle, including promotion of myoblast differentiation and protection from atrophy, in all likelihood by activating a common receptor. Also, UnAG promotes muscle regeneration, stimulation of muscle satellite cell activity, and activates autophagy and mitophagy at higher extent than AG. Age-dependent hypoghrelinemia could participate in the establishment of sarcopenia by facilitating the progression of muscle atrophy and limiting skeletal muscle regeneration capability.

Here, we show that both the deletion of the ghrelin gene (Ghrl KO) and the lifelong overexpression of UnAG (Tg) in mice attenuated the age-associated decline in muscle mass and functionality, seen as larger myofiber areas, lower levels of Atrogin-1, and increased mitochondrial functionality compared to old wild type (WT) animals. Also, both Ghrl KO and Tg animals displayed reduced systemic inflammation and maintenance of brown adipose tissue functionality. While old Tg mice apparently preserved the characteristics of young animals, Ghrl KO mice features deteriorate with aging. However, young Ghrl KO mice show more favorable features compared to WT animals that result, on the whole, in better performances in aged Ghrl KO mice. Altogether, the data collected suggest that, in Ghrl KO mice, it is the lack of AG that is the major determinant factor of their overall better conditions and advocate for the design of analogs to UnAG rather than AG to therapeutically treat sarcopenia in humans.

Using Direct Conversion of Cells to Investigate the Behavior of Aging Tissues

The process of reprogramming used to produce induced pluripotent stem cells erases many of the marks of aging in cells taken from old tissues, such as epigenetic changes and declining mitochondrial function. This may prove to be the basis for therapies based on reprogramming, but it is also very inconvenient for researchers who want to study how old cells and tissues behave in detail. Thus scientists here use a process of direct conversion, programming one cell type to become another without inducing a stem cell state, in order to retain the features of old tissue. That allows the identification of differences between old and young cellular metabolism, and run initial tests of potential interventions in cell cultures.

Research into aging vasculature has been hampered by the fact that collecting blood vessel cells from patients is invasive, but when blood vessel cells are created from special stem cells called induced pluripotent stem cells, age-related molecular changes are wiped clean. In 2015, however, researchers showed that fibroblasts could be directly reprogrammed into neurons, skipping the induced pluripotent stem cell stage that erased the cells’ aging signatures. The resulting brain cells retained their markers of age, letting researchers study how neurons change with age. In new work, researchers applied the same direct-conversion approach to create two types of vasculature cells: vascular endothelial cells, which make up the inner lining of blood vessels, and the smooth muscle cells that surround these endothelial cells.

The researchers used skin cells collected from three young donors, aged 19 to 30 years old, three older donors, 62 to 87 years old, and 8 patients with Hutchinson-Gilford progeria syndrome (HGPS), a disorder of accelerated, premature aging often used to study aging. The resulting induced vascular endothelial cells (iVECs) and induced smooth muscle cells (iSMCs) showed clear signatures of age. 21 genes were expressed at different levels in the iSMCs from old and young people, including genes related to the calcification of blood vessels. 9 genes were expressed differently according to age in the iVECs, including genes related to inflammation.

To test the utility of the new observations, the researchers tested whether blocking BMP4 – which had been present at higher levels in smooth muscle cells developed from people with HGPS – could help treat aging blood vessels. In smooth muscle cells from donors with vascular disease, antibodies blocking BMP4 lowered levels of vascular leakiness – one of the changes that occurs in vessels with aging. The findings point toward new therapeutic targets for treating both progeria and the normal age-related changes that can occur in the human vascular system.

Targeting Inflammatory Microglia in the Treatment of Neurodegenerative Disease

The immune cells of the central nervous system are distinct from those of the rest of the body. Innate immune cells such as microglia become increasingly inflammatory with advancing age, and this is very disruptive of tissue function in the brain. This progression into a state of chronic inflammation is an important component of many neurodegenerative conditions. Some of this is due to growing levels of cellular senescence in these cell populations, and with the advent of senolytic therapies to selectively destroy senescent cells, some reversal of neurodegeneration has been demonstrated in animal models. Not all inflammatory microglia are senescent, however, and it seems likely that the causes of the more general overactivation of such cells will also need to be addressed.

Advances in nanotechnology have enabled the design of nanotherapeutic platforms that could address the challenges of targeted delivery of active therapeutic agents to the central nervous system (CNS). While the majority of previous research studies on CNS nanotherapeutics have focused on neurons and endothelial cells, the predominant resident immune cells of the CNS, microglia, are also emerging as a promising cellular target for neurodegeneration considering their prominent role in neuroinflammation. Under normal physiological conditions, microglia protect neurons by removing pathological agents. However, long-term exposure of microglia to stimulants will cause sustained activation and lead to neuronal damage due to the release of pro-inflammatory agents, resulting in neuroinflammation and neurodegeneration.

This perspective highlights criteria to be considered when designing microglia-targeting nanotherapeutics for the treatment of neurodegenerative disorders. These criteria include conjugating specific microglial receptor-targeting ligands or peptides to the nanoparticle surface to achieve targeted delivery, leveraging microglial phagocytic properties, and utilizing biocompatible and biodegradable nanomaterials with low immune reactivity and neurotoxicity. In addition, certain therapeutic agents for the controlled inhibition of toxic protein aggregation and for modulation of microglial activation pathways can also be incorporated within the nanoparticle structure without compromising stability. Overall, considering the multifaceted disease mechanisms of neurodegeneration, microglia-targeted nanodrugs and nanotherapeutic particles may have the potential to resolve multiple pathological determinants of the disease and to guide a shift in the microglial phenotype spectrum toward a more neuroprotective state.

The Aging of Macrophages Impairs Peripheral Nerve Regeneration

Macrophages of the innate immune system, cells derived from monocytes, are involved in many processes in tissue beyond merely hunting down invading pathogens. They are also important to the processes of tissue maintenance regeneration following injury. Like all aspects of the immune system, macrophage behavior becomes dysregulated with age, a consequence of changes in the signaling environment that result from the accumulation of molecular damage that causes aging. Here, researchers demonstrate that this aging of the immune system degrades the ability of the peripheral nervous system to regenerate, and that exposing macrophages to a more youthful tissue environment reverses some of this lost regenerative capacity. Further, they identify a little of the regulatory biochemistry involved in this aspect of degenerative aging.

The regenerative capacity of injured peripheral nerves is diminished with aging. To identify factors that contribute to this impairment, we compared the immune cell response in young versus aged animals following nerve injury. First, we confirmed that macrophage accumulation is delayed in aged injured nerves which is due to defects in monocyte migration as a result of defects in site-specific recruitment signals in the aged nerve. Interestingly, impairment in both macrophage accumulation and functional recovery could be overcome by transplanting bone marrow from aged animals into young mice. That is, upon exposure to a youthful environment, monocytes/macrophages originating from the aged bone marrow behaved similarly to young cells.

Transcriptional profiling of aged macrophages following nerve injury revealed that both pro- and anti-inflammatory genes were largely downregulated in aged compared to young macrophages. One ligand of particular interest was macrophage-associated secreted protein (MCP1), which exhibited a potent role in regulating aged axonal regrowth in vitro. Given that macrophage-derived MCP1 is significantly diminished in the aged injured nerve, our data suggest that age-associated defects in MCP1 signaling could contribute to the regenerative deficits that occur in the aged nervous system.

Lowered Body Temperature is Important in the Beneficial Calorie Restriction Response

Calorie restriction lowers body temperature in mammals, but most research on how reduced calorie intake produces benefits to long-term health and longevity has focused on nutrient sensing as the primary trigger for the upregulation of stress responses and other helpful changes to cellular metabolism. Here, researchers demonstrate that reduced body temperature is in fact an important trigger mechanism, possible more so than nutrient sensing, as keeping calorie restricted mice warm eliminates much of the beneficial metabolic adaptation to reduced nutrient levels.

Cutting calories significantly may not be an easy task for most, but it’s tied to a host of health benefits ranging from longer lifespan to a much lower chance of developing cancer, heart disease, diabetes, and neurodegenerative conditions such as Alzheimer’s. One consistent observation is that when mammals consume less food, their body temperature drops. It’s evolution’s way of helping us conserve energy until food is available again. It makes sense, considering that up to half of what we eat every day is turned into energy simply to maintain our core body temperature.

Previous work showed that temperature reduction can increase lifespan independently of calorie restriction – and that these effects involve activation of certain cellular processes, most of which remain to be identified. On the flip side, studies have shown that preventing body temperature from dropping can actually counteract positive effects of calorie restriction. Notably, in an experiment involving calorie-restricted mice, anti-cancer benefits were diminished when core body temperature remained the same. “It’s not easy to discern what’s driving the beneficial changes of calorie restriction. Is it the reduced calories on their own, or the change in body temperature that typically happens when one consumes fewer calories? Or is it a combination of both?”

In the new research, scientists compared one group of calorie-restricted mice housed at room temperature, about 68 degrees Fahrenheit (22 degrees Celsius), to another group housed at 86 degrees (30 degrees Celsius). The warmer environment invoked “thermoneutrality,” a state at which most animals cannot easily reduce their body temperature. The team evaluated the mice by measuring their metabolites, or chemicals released by the animals’ metabolism. Through this, they were able to look for molecules in the bloodstream and in the brain that are changed by the reduction of either nutrients or body temperature. “The data we collected showed that temperature has an equal or greater effect than nutrients on metabolism during calorie restriction.”

Metformin Found to Reduce Liver Inflammation

Metformin produces a modest and unreliable extension of life in animal models, and human data shows a small increase in life span in diabetic patients. This is thought to work as a calorie restriction mimetic drug, triggering one slice of the beneficial response to a reduced nutrient intake. Researchers here dig further in the biochemistry of the drug, and find that it reduces liver inflammation in addition to other, known effects. This is interesting, and suggestive that any benefits it produces are going to be much smaller in healthier older adults with lower levels of chronic inflammation. It doesn’t change the fact that metformin does have only a small and unreliable effect on life span per the existing data, and is thus not where we should be focusing our attention.

Researchers have known for 20 years that metformin activates a metabolic master switch, a protein called AMPK, which conserves a cell’s energy under low nutrient conditions, and which is activated naturally in the body following exercise. Twelve years ago, researchers discovered that in healthy cells, AMPK starts a cascade effect, regulating two proteins called Raptor and TSC2, which results in a block of the central pro-growth protein complex called mTORC1 (mammalian target of rapamycin complex 1). These findings helped explain the ability of metformin to inhibit the growth of tumor cells.

But in the intervening years, many additional proteins and pathways that metformin regulates have been discovered, drawing into question which of the targets of metformin are most important for different beneficial consequences of metformin treatment. Indeed, metformin is currently entering clinical trials in the United States as a general anti-aging treatment because it is effects are so well established from millions of patients and its side effects are minimal. But whether AMPK or its targets Raptor or TSC2 are important for different effects of metformin remains poorly understood.

In the new work, in mice, researchers genetically disconnected the master protein, AMPK, from the other proteins, so they could not receive signals from AMPK, but were able to otherwise function normally and receive input from other proteins. When these mice were put on a high-fat diet triggering diabetes and then treated with metformin, the drug no longer had the same effects on liver cells as it did in normally diabetic animals, suggesting that communication between AMPK and mTORC1 is crucial for metformin to work. By looking at genes regulated in the liver, the researchers found that when AMPK couldn’t communicate with Raptor or TSC2, metformin’s effect on hundreds of genes was blocked. Some of these genes were related to lipid metabolism, helping explain some of metformin’s beneficial effects. But surprisingly, many others were linked to inflammation. Metformin, the genetic data showed, normally turned on anti-inflammatory pathways and these effects required AMPK, TSC2, and Raptor.

Metformin and exercise elicit similar beneficial outcomes, and research has previously shown that AMPK helps mediate some of the positive effects of exercise on the body. “If turning on AMPK and shutting off mTORC1 are responsible for some of the systemic benefits of exercise, that means we might be able to better mimic this with new therapeutics designed to mimic some of those effects.”

Geroscience and Ovarian Aging

The geroscience view of the treatment of aging isn’t limited to the reuse of existing drugs that happen to upregulate stress responses in ways that modestly slow aging, but this is the near entirely the focus of those researchers who publish on the topic. Unfortunately the effect size of this approach to aging is small, and diminishes as species life span increases. We know the upper limits of what can be achieved with the beneficial stress response induced by calorie restriction in humans, and we know that it won’t really add more than a couple of years to human life spans. Better strategies exist, based on the development of biotechnologies that repair the underlying cell and tissue damage that causes aging. Repair can in principle achieve rejuvenation, not just a modest slowing of aging, and that rejuvenation has already been demonstrated in animal models for the repair-based approach of removing senescent cells from old tissues.

In women 35 years and older the incidences of infertility, aneuploidy, and birth defects dramatically increase. These outcomes are a result of age-related declines in both ovarian reserve and oocyte quality. In addition to waning reproductive function, the decline in estrogen secretion at menopause contributes to multi-system aging and the initiation of frailty. Both reproductive and hormonal ovarian function are limited by the primordial follicle pool (PFP), which is established in utero and declines irreversibly until menopause. Because ovarian function is dependent on the PFP, an understanding of the mechanisms that regulate follicular growth and maintenance of the PFP is critical for the development of interventions to prolong the reproductive lifespan.

Manipulating the rate of aging and delaying the onset of aging-related diseases have been the makeup of medical, scientific, and pseudo-scientific pursuits throughout history. However, it is not until relatively recently, in the later part of the 20th and early 21st centuries, that the molecular targets and geroscience approaches needed to make this a reality have been elucidated. For example, improvements in reproductive function after rapamycin treatment are evident in studies of physiologic murine aging. A 2-week course of rapamycin in healthy mice improved primordial follicle count, oocyte morphology, and mitochondrial activity. In mating studies, after 12 months of age, when the control mice began to experience age-related infertility, the rapamycin-treated mice retained fertility and continued to have pups. Equally, a 12-month course of resveratrol in mice increased primordial follicle counts, litter size, and oocyte quality at advanced ages. Additionally, a specific SIRT1 activator SRT1720 administered to mice suppressed the activation of primordial follicles and increased the ovarian reserve by activating SIRT1 and inhibiting mTOR signaling.

Multiple pathways, many of them nutrient-sensing, converge in the mammalian ovary to regulate the quiescence and activation of primordial follicles. The PI3K/PTEN/AKT/FOXO3 and mTOR pathways appear to be central to the regulation of the primordial follicle pool; however, GH/IGF-1 and H2S may also play a role. A delicate balance of primordial follicle activators and suppressors must be maintained in order to allow for continued ovulation while preventing rapid depletion of the ovarian reserve. The behavioral and pharmacologic interventions that prevent primordial follicle activation, including DR and rapamycin, cause infertility for the duration of the intervention. In order for these interventions to be useful clinically, the resulting period of infertility must be reversible, and the treatments must confer long-term benefits after a relatively short duration of use.

Long Term mTORC1 Inhibition Slows Muscle Aging in Mice via Preservation of Neuromuscular Junctions

Sarcopenia is the name given to the characteristic loss of muscle mass and strength that occurs in later life, the result of numerous contributing processes of damage and decline. Researchers here find that long-term treatment with rapamycin, and thus likely other more targeted approaches to mTORC1 inhibition, slows the onset of sarcopenia in mice by preserving the function of neuromuscular junctions, the links between nerves and muscles. The most important contributing cause of sarcopenia is likely to be a slowdown in muscle stem cell activity. Interestingly, these stem cell populations appear to remain viable, but are increasingly quiescent in response to the damaged and inflammatory environment of aged tissues. This work suggests that damage and declining function of neuromuscular junctions should be given a greater weight than previously considered, however.

Recently, nine processes involved in aging were proposed, namely cellular senescence, stem cell exhaustion, genomic instability, telomere attrition, loss of proteostasis, deregulation of nutrient sensing, epigenetic alterations, mitochondrial dysfunction, and altered intracellular communication. Each biological process fulfils three hallmark criteria: (1) it occurs during normal aging, (2) intensifying the process accelerates aging, and (3) dampening the process delays aging. Overactivity of the mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) is central to many of these processes, and dampening mTORC1 activity by its allosteric inhibitor rapamycin is one of the most effective interventions to prolong life. However, mTORC1 activity is also required for muscle hypertrophy. Therefore, there is concern that suppressing mTORC1 to extend lifespan could be at the expense of skeletal muscle function, thereby extending the “poor-quality” period of life.

In previous work, we have shown that mTORC1 activity must be finely balanced in skeletal muscle. Here, we demonstrate that long-term rapamycin treatment is overwhelmingly positive in aging skeletal muscle, preserving muscle size, function, and neuromuscular junction (NMJ) integrity. Interestingly, responsiveness to rapamycin differs between muscles, suggesting that the primary drivers of age-related muscle loss may differ between muscles. To dissect the key signaling nodes associated with mTORC1-driven sarcopenia, we create a comprehensive multimuscle gene expression atlas from (1) adult (10-months old), (2) geriatric (30-months old), and (3) geriatric, rapamycin-treated mice using mRNA-seq. Our data point to age-related NMJ instability as a focal point of mTORC1-driven sarcopenia. Maintenance of NMJ structure and transmission efficiency is crucial for preserving muscle function at high age.