Fight Aging!

First generation interventions to target aging are presently in clinical development, or available but not yet widely used. They include senolytic drugs, and a whole range of approaches to upregulate various stress response mechanisms and improve mitochondrial function, among other options. Second generation interventions are under investigation in the scientific community, but remain some years away from earnest clinical development for one reason or another. Most of the possible approaches to the wholesale, reliable replacement of cell populations, for example.

The best of plausible futures is the one in which the most effective of these first and second generation interventions (a) become widely used and (b) produce significant gains in the healthy human life span, of ten to twenty years or more. We'll know one way or another by 2040, and the signs of efficacy should be there earlier than that. I'd wager that we could know by the early 2030s as to whether or not senolytics have a strong effect on human life expectancy in old age, for example. A five year study would be long enough to determine an outcome, but it will take a few years from where we are now in order to get such a study launched. The research community is still waiting on the arrival of compelling human data - to match the great animal data - on suppression of inflammation and improvement of tissue function throughout the body resulting from senolytic treatment.

Cancer will be a consequence of this success. The declines of late life in our species evolved in large part to lower the risk of death by cancer, by reducing cellular activity in damaged environments, at the cost of a slower and more drawn out death by organ failure. Many of the early therapies targeting function in old age are essentially compensatory, dialing up stem cell function or tissue function despite damage, overriding the normal reactions of the body to raised levels of cell and tissue damage. Some therapies do aim to repair cell and tissue damage, and will produce much the same outcome in terms of increased function, but any given collection of treatments will not repair all of the damage. In particular, mutational nuclear DNA damage will be challenging to repair.

Cancer is a numbers game. How many cells, how much cellular activity, how much damage, how long a span of time. Cancer risk is a combination of factors: stochastic mutation in nuclear DNA, the spread of mutations into somatic mosaicism, the inflammatory environment of aged tissues, driven in large part by senescent cells, and the growing incapacity of the aged immune system. To the extent that therapies can address these factors, cancer rates will fall. Cancer is not going to vanish entirely any time soon, however, given the mutation issue. Cancer is an inevitability on any time frame that is long enough, living in a body with nuclear DNA that is damaged enough.

Thus we should all get used to the idea that our lifetime risk of cancer will be notably higher than that of our ancestors, and plan accordingly. Robust, reliable approaches to detecting and destroying cancer are a very necessary part of the panoply of rejuvenation therapies that will be produced over the next few decades. Very broad anti-cancer technologies, such as interference in telomere lengthening, that can be applied to all cancers, will be needed in order to make cost-effective, rapid progress towards the medical control of cancer.

Ultimately, cancer will not be feared by long-lived individuals with access to modern medical technology. A great deal of work remains to get to that point. Once there, however, the cancers that we will suffer - briefly, before they are dealt with efficiency and quickly - will be badges of honor, a mark of the degree to which we have fought back degenerative aging.

The accumulation of senescent cells throughout the body with age contributes to the chronic inflammation of aging, as well as to many age-related conditions. Clearance of these cells produces a sizable and beneficial reversal of aspects of aging and the progression of age-related disease in mice. We will soon enough know whether this is also true in humans. Given the number of biotech companies presently working on senolytic therapies capable of targeted destruction of senescent cells, many clinical trials for senolytics will be undertaken in the years ahead. As noted below, osteoporosis is one of the age-related conditions in which growing numbers of senescent cells are implicated as a contributing cause.

Substantial alterations in bone architecture occur with aging, including decreases in trabecular thickness and number, cortical bone loss and porosity, and increase in marrow adiposity. These changes reflect imbalances in bone remodeling, favoring a net loss of bone caused predominately by increased osteoclast activity in postmenopausal women, as well as both poor bone formation and increased osteoclast activity in older men and women. Cellular senescence and apoptosis of osteoblasts and osteocytes account for much of the aging phenotype in bone, although appear to be independent of estrogen-mediated effects.

There is growing evidence to suggest that cellular senescence in bone can be triggered by reactive oxygen species, DNA damage, telomere dysfunction, and heterochromatin changes, depending on the cell type. miRNAs serve to modulate critical switching points, such as those between osteogenesis and adipogenesis, and aspects of the senescence program. The senescence-associated secretory phenotype (SASP) likely mediates local and even distant deleterious effects of senescent cells, especially by myeloid cells and osteocytes. Radiation-induced bone loss provides an accelerated aging bone model that recapitulates many aspects of age-related bone loss. With both physiological and premature bone aging, genetic and pharmacologic approaches to clearing senescent cells prevent, delay, or ameliorate osteoporosis in mouse models. Senolytic compounds are currently being evaluated in interventional clinical trials.

Link: https://doi.org/10.1002/jbm4.10488

Senescent cells accumulate with age throughout the body. Their secreted signals generate chronic inflammation, change surrounding cellular behavior for the worse, and disrupt tissue maintenance and tissue function. In mice, targeted removal of these cells with senolytic drugs reverses aspects of aging and extends life span. In humans, early clinical trials of these drugs are underway. As noted in this short review paper, there is evidence for cellular senescence to be involved in vascular aging. Senescent cells may contribute to the formation of aneurysms. Senescent macrophages may accelerate the progression of atherosclerosis. Senescent cells promote vascular calcification. And so forth.

Since the initial clinical trials for senolytic drugs are focused on other age-related conditions, it may be some years before there is robust data for vascular aging to show how well the results in mice translate to humans. The first generation senolytics are easily obtained compounds, however, and at least one of these treatments comes with human data to show that it does indeed clear much the same fraction of senescent cells as it does in mice. The self-experimentation and medical tourism communities will be employing these treatments well in advance of further formal publications on their efficacy.

The endothelial cell (EC) monolayer forms the inner cellular lining of all blood vessels forming a critical interface between blood and tissue. Vascular endothelium is involved in physiological functions, which include regulation of blood fluidity, hemostasis and clotting, vascular tone, immune responses, inflammation, angiogenesis, and metabolism. Dysfunction of the endothelium is a major contributor to cardiovascular diseases (CVD) such as stroke, atherosclerosis, hypertension, and diabetes. Chronological aging is the dominant risk factor for CVD, cancer and neurodegenerative diseases and indeed endothelial dysfunctions including arterial stiffening, impaired neovascularization, and loss of tissue-barrier function are evident in age-related disease.

EC dysfunction is a well-accepted hallmark of age-related vascular dysfunction, with the initiation of abnormal inflammatory and thrombotic circuits, arterial stiffening and oxidative stress being central to its biology. Importantly, for our understanding of vascular aging, senescent EC accumulate in aging tissues and contribute to tissue dysfunction.

The field of senolytics, drugs that selectively eliminate senescent cells, is gaining momentum. Dasatinib and Quercetin (D+Q) were some of the first senolytics, which remove senescent cells in vitro and in progeroid mice through targeting of the anti-apoptotic pathways in senescence. Long term oral treatment of D+Q have been shown to improve vascular function in aged or atherosclerotic mice. The D+Q combination has been shown to efficiently reduce senescence cell burden in phase I trials for several senescence-related diseases such as diabetic kidney disease.

Although senescence was initially considered as an all-encompassing phenotypic change, it is now apparent that each cell type exhibits an unique and distinguishing senescence phenotype, one that may also be tissue specific. Hence our understanding of endothelial senescence is still in its infancy. Current findings have indicated that specific depletion of senescent cells reverses age-related changes and prolongs life span. However, caution should be urged as cellular senescence also plays important physiological roles such as in tissue development, wound healing, and tumor inhibition. To achieve optimal success in targeting senescence it will be imperative to have a thorough knowledge of the senescent cell type at play in disease, and their spatiotemporal expression in order to deliver the most appropriate senolytic, senomorphic or drug combination.

Link: https://doi.org/10.1530/VB-20-0013

The inhibition of CDC42 is starting to look like a most interesting intervention, based on the animal data produced over the past decade or so. A small molecule approach to CDC42 inhibition, using CASIN, has been assessed in a number of animal studies focused on the hematopoietic stem cell population responsible for generating blood cells and immune cells. Treatment of mice with CASIN results in improved hematopoietic stem cell function, improved immune function, and extended life span. The life span extension was achieved following a single course of treatment with CASIN in middle-aged mice, suggesting that a one-time intervention can produce a lasting improvement in the immune system over the remainder of later life. The state of the immune system itself is, of course, very influential on tissue function and the progression of aging and age-related disease.

Today's open access paper reports on a study focused on a different stem cell population, the intestinal stem cells that support the lining of the gut. Like all stem cell populations, intestinal stem cells decline with age. They become less active, more damaged, and their niches change in ways that promote this lost function. That CASIN treatment can help intestinal stem cell function, and produce improvement in the state of the intestinal epithelium as a result, suggests that the benefits to this therapy are not solely due to improved immune function. If seen to affect two stem cell populations, it may influence numerous other stem cell populations as well.

Suppression of elevated Cdc42 activity promotes the regenerative potential of aged intestinal stem cells

The regenerative capacity of intestine decreases upon aging. Organ homeostasis in the intestine is maintained by intestinal stem cells (ISCs). A decline in ISC function is a main reason for the impaired regeneration of intestinal epithelium upon aging. ISCs express the marker gene Lgr5 and are located next to differentiated Paneth cells at the base of the intestinal crypt. To function properly under homeostasis, ISCs differentiate into highly proliferative transient amplifying (TA) cells. Upon their migration from the crypt base to the villus, TA cells further differentiate into mature cell types including cells in the intestinal villus made of enterocytes, goblet cells, and enteroendocrine cells.

The small RhoGTPase Cdc42 cycles between an active, GTP-bound form (Cdc42-GTP) and an inactive, GDP-bound form. It is thought that biological activity of Cdc42 is regulated by its active form, i.e., the level of Cdc42-GTP. The relative ratio of active Cdc42 is elevated in various tissues of aged mice compared to that of young mice, whereas animals in which Cdc42 activity is increased by genetic means show diverse premature aging phenotypes. It is possible that there is a causative link between Cdc42 activity and aging, and increased Cdc42 activity has indeed been reported to be a causative stem cell intrinsic mechanism for the aging of hematopoietic stem cells (HSCs).

For ISCs, their regeneration capacity declines upon aging, and multiple mechanisms including changes in Wnt signaling could be involved in the process. We show here that an aging-associated increase in the Cdc42 activity in ISCs causes a decline in ISC function and impairs intestinal epithelial regeneration. Suppression of Cdc42 activity can ameliorate ISC regeneration in vitro, and pharmacologic targeting of Cdc42 critically enhances intestinal regeneration upon stress in vivo up on aging. Our studies imply that a tight regulation of the Cdc42 activity is critical for maintaining tissue homeostasis within the intestine during aging and that suppression of aging-related increased Cdc42 activity allows for enhanced tissue regeneration in vivo.

There is a growing level of interest and funding for the goal of reversible cryopreservation of whole organs. If achieved, this would radically improve the logistics of organ donation, allowing organs to be kept indefinitely before use. Proof of principle demonstrations have been carried out, but the field has lacked the funding and impetus to rapidly build upon that starting point. Hopefully this will change. The ability to reliably vitrify and thaw large tissue sections with minimal ice crystal formation, cell death, or other structural damage will add legitimacy to the goal of human cryopreservation, storing patients at the time of death to allow the possibility of future revival in an environment of far more capable biotechnology.

When scientists in the 1950s tried to cool hamsters to 0°C and rewarm them, it didn't go great. In 2002, things looked rosier when a scientist chilled a single rabbit kidney down to -130°C, then rewarmed it and transplanted it into a live rabbit, where it worked for 48 days. Then not much else succeeded for the next decade. Chilling and re-warming organs, it turns out, is really, really hard. Ice crystals that form during cooling and re-warming cause massive physical damage to cells and whole tissues.

To nudge the field forward, in 2014 a group of entrepreneurs formed the nonprofit Organ Preservation Alliance (OPA). In the years since, the OPA coordinated numerous conferences and publications and prompted the creation of a National Science Foundation technology roadmap for organ cryopreservation, all of which bolstered more than $100 million in new cryobiology funding from U.S. science agencies, donors, and industry. Now, in what OPA sees as a culmination of their efforts, the organization is launching a philanthropic fund to support two academic research centers focused on cryopreservation. "It's been a renaissance for the field of cryobiology. These two centers build on that momentum, and new technologies have come into sharp focus within the same timeframe."

Resarchers will focus on safely cooling tissues and organs by infusing the vasculature and surroundings with cryoprotective solutions and iron oxide nanoparticles coated with silica. After rapid cooling to a very low temperature, a process called vitrification, the organ or tissue is stored. Upon rewarming, the team activates the distributed nanoparticles via a radiofrequency field, heating the cryopreserved tissue rapidly and uniformly. Finally, the cryoprotective agents and nanoparticles can be safely removed prior to transplant or other biomedical use. "Scientists are coming back to ideas they had in the 1980s, but now with the right technology to carry them out. It's incredibly exciting. Back then, we didn't have the right tools, but now it feels like we really do. We hope we're about to make this really big step forward."

Link: https://spectrum.ieee.org/the-human-os/biomedical/devices/lasers-and-lunar-arks-cryopreservation-heats-up

Declining levels of NAD+ in cells is one of the proximate causes of loss of mitochondrial function with age. A number of approaches to increasing levels of NAD+ in cells involve using supplements that are derived from vitamin B3. Nicotinamide mononucleotide (NMN) is one of these, but has to date far less published human evidence for its effects than is the case for nicotinamide riboside (NR), making the small study noted here interesting. In general, the evidence for vitamin B3 derived compounds to increase NAD+ in older people is good, while the evidence for that increase to then produce benefits to health is mixed at best. For further consideration, regular exercise appears to be better at increasing NAD+ levels than this sort of supplementation, based on human trial data, and we have a fairly good idea as to the effect size of exercise when it comes to mortality and risk of age-related disease.

A small clinical trial of postmenopausal women with prediabetes shows that the compound NMN (nicotinamide mononucleotide) improved the ability of insulin to increase glucose uptake in skeletal muscle, which often is abnormal in people with obesity, prediabetes or Type 2 diabetes. NMN also improved expression of genes that are involved in muscle structure and remodeling. However, the treatment did not lower blood glucose or blood pressure, improve blood lipid profile, increase insulin sensitivity in the liver, reduce fat in the liver or decrease circulating markers of inflammation as seen in mice.

Among the women in the study, 13 received 250 mg of NMN orally every day for 10 weeks, and 12 were given an inactive placebo every day over the same period. "Although our study shows a beneficial effect of NMN in skeletal muscle, it is premature to make any clinical recommendations based on the results from our study. Normally, when a treatment improves insulin sensitivity in skeletal muscle, as is observed with weight loss or some diabetes medications, there also are related improvements in other markers of metabolic health, which we did not detect in our study participants."

The remarkable beneficial effects of NMN in rodents have led several companies in Japan, China and in the U.S. to market the compound as a dietary supplement or a neutraceutical. The U.S. Food and Drug Administration is not authorized to review dietary supplement products for safety and effectiveness before they are marketed, and many people in the U.S. and around the world now take NMN despite the lack of evidence to show clinical benefits in people.

Link: https://medicine.wustl.edu/news/anti-aging-compound-that-improves-metabolic-health-in-mice-improves-muscle-glucose-metabolism-in-people/

In today's research materials, researchers present an approach to cell therapy involving the delivery of progenitor cells that are biased to differentiate into astrocytes. Further, the astrocytes so produced are primed to undertake repair activities in the brain. This sort of regenerative approach is in principle applicable to a range of issues, from structural damage to the brain, such as that resulting from injury or stroke, to more subtle issues such as demyelination and the progressively worsening consequences of age-related neurodegeneration.

The advantage of progenitor cells and stem cells, particularly the pluripotent cells that are now easily manufactured by any competent lab, is that they can take on the characteristics of many different cell types. This is also the disadvantage when one wants a very particular type of cell and class of cell behavior. In principle, the robust methods of production of pluripotent cells make it more cost effective to turn out any cell type needed. In practice, the challenge lies in finding the recipe of signals and environment to ensure that the resulting differentiated cells perform in the desired way. This recipe is different for every scenario, and this is one of the reasons why progress towards cell based regenerative therapies is slower than we would all like it to be.

Stem cell therapy promotes recovery from stroke and dementia in mice

The two most common causes of dementia are Alzheimer's disease and white matter strokes - small strokes that accumulate in the connecting areas of the brain. Currently, there are no therapies capable of stopping the progression of white matter strokes or enhancing the brain's limited ability to repair itself after they occur. Now a new study identifies a cell therapy that can stop the progressive damage caused by the disease and stimulate the brain's own repair processes.

The cells used in the therapy are a specialized type of glial cells, which are cells that surround and support neurons in the central nervous system. Researchers evaluated the effects of their glial cell therapy by injecting it into the brains of mice with brain damage similar to that seen in humans in the early to middle stages of dementia. Upon injection, the cells traveled to damaged areas of the brain and secreted growth factors that stimulated the brain's stem cells to launch a repair response. Activating that repair process not only limited the progression of damage, but it also enhanced the formation of new neural connections and increased the production of myelin - a fatty substance that covers and protects the connections.

Patient-derived glial enriched progenitors repair functional deficits due to white matter stroke and vascular dementia in rodents

Astrocytes, axons, and myelin are subjected to major damage during subcortical white matter stroke (WMS), a debilitating disorder leading to cognitive and motor impairments. Previous studies have shown that immature astrocyte transplantation could promote remyelination in rodent models. Now, a team has used a model of WMS in mice to demonstrate that transplantation of glial enriched progenitor cells differentiated from human-induced pluripotent stem cells (hiPSC-GEPs) shortly after stroke matured into a mature astrocyte phenotype and had therapeutic effect on axonal damage, demyelination, and cognitive impairments more effectively than hiPSC-derived neuronal precursor cells. The results suggest that astrocyte precursors have therapeutic potential in stroke.

A great deal of time and effort has been spent on investigating the biochemistry of sirtuins in numerous species, with as yet very little to show for it in practical terms. Early attempts to produce viable age-slowing interventions via upregulation of sirtuin 2 were a comprehensive failure, and it is entirely plausible that recent interest in sirtuin 6 will go the same way. This class of metabolic tinkering has a terrible track record, mixed results in mice that then fail to translate to humans, and the reasonable expectation is that this will continue to be the case for the foreseeable future.

The role of sirtuins in senescence was discovered in budding yeast, where overexpression of SIR2 increases replicative lifespan. Subsequently, It was reported that elevated sirtuin levels increase lifespan in the nematode C. elegans and the fruitfly Drosophila, indicating an evolutionarily ancient role of sirtuins in longevity assurance. Mammals contain seven sirtuins, SIRT1-7, which are categorized by their different subcellular localization, unique binding substrates, and diverse enzymatic activities. Recently the direct role of SIR2 in aging and lifespan extension has been disputed, but the overwhelming majority of significant results still support a potential role for SIRT6 in regulating mammalian lifespan.

SIRT6 was shown to extend lifespan in mammals, while deficiency of SIRT6 was associated with progeria, an accelerated aging disorder. Studies have confirmed the important roles for SIRT6 in protecting against aging and disease pathologies: SIRT6-deficient mice are small and have severe metabolic defects, and by 2-3 weeks of age, they develop abnormalities that are usually associated with aging. However, SIRT6 overexpression led to an increase in lifespan in male mice. Mechanistically, SIRT6, being a histone deacetylase, inhibits the transcription of transcription factors related to senescence, maintains the structure of telomere chromatin, prevents genomic instability after DNA damage, and protects cells from senescence.

Link: https://doi.org/10.3389/fcell.2021.641315

Myostatin is one of the better targets for enhancement therapies from the point of view of feasibility and existing data on its effects. Myostatin suppresses muscle growth via intracellular signaling. A range of possible methods exist to interfere in this process, some of which have been trialed in human patients: reducing production of myostatin, binding to circulating myostatin with antibodies to ensure clearance, preventing myostatin from binding to cell surface receptors in other ways, upregulation of follistatin, an antagonist to myostatin, and so forth. Myostatin loss of function mutants, natural and artificial, exist for a range of mammalian species, including humans. Beyond a much greater than usual muscle growth, there do not appear to be obvious long-term issues in these individuals.

Current research findings in humans and other mammalian and non-mammalian species support the potent regulatory role of myostatin in the morphology and function of muscle as well as cellular differentiation and metabolism, with real-life implications in agricultural meat production and human disease. Myostatin null mice (mstn-/-) exhibit skeletal muscle fiber hyperplasia and hypertrophy whereas myostatin deficiency in larger mammals like sheep and pigs engender muscle fiber hyperplasia. Myostatin's impact extends beyond muscles, with alterations in myostatin present in the pathophysiology of myocardial infarctions, inflammation, insulin resistance, diabetes, aging, cancer cachexia, and musculoskeletal disease.

In this review, we explore myostatin's role in skeletal integrity and bone cell biology either due to direct biochemical signaling or indirect mechanisms of mechanotransduction. In vitro, myostatin inhibits osteoblast differentiation and stimulates osteoclast activity in a dose-dependent manner. Mice deficient in myostatin also have decreased osteoclast numbers, increased cortical thickness, cortical tissue mineral density in the tibia, and increased vertebral bone mineral density. Further, we explore the implications of these biochemical and biomechanical influences of myostatin signaling in the pathophysiology of human disorders that involve musculoskeletal degeneration.

The pharmacological inhibition of myostatin directly or via decoy receptors has revealed improvements in muscle and bone properties in mouse models of osteogenesis imperfecta, osteoporosis, osteoarthritis, Duchenne muscular dystrophy, and diabetes. However, recent disappointing clinical trial outcomes of induced myostatin inhibition in diseases with significant neuromuscular wasting and atrophy reiterate complexity and further need for exploration of the translational application of myostatin inhibition in humans.

Link: https://doi.org/10.3389/fgene.2021.662908

Today I'll point out a high quality commentary on what we might take away from the War on Cancer, launched 50 years ago. In the longevity advocacy community, the notable past success in building a cancer research community, as well as in persuading the public to support large-scale efforts to bring an end to cancer, are viewed as an aspirational goal. Over the years there has been talk of attempting to reproduce these successes in order to engineer public support for a War on Aging. There were many moving parts to the War on Cancer: decades of preliminary patient advocacy and lobbying; the evolution of public attitudes towards cancer and cancer research; progress in science and funding; the challenges inherent in the growth of a truly massive research community; the creation of a funding ecosystem to power that broad range of research. Much might be learned from an examination of each.

There are other lessons we might learn here, however, such as the modes of failure that emerge from focusing on diseases of aging, such as cancer, rather than on aging itself. Or that the wrong approach to a problem can absorb any amount of funding to produce only incremental progress. Diseases of aging are caused by the mechanisms of aging, yet little to no work made the deliberate effort to target those mechanisms until comparatively recently. Attempting to treat the disease, rather than its cause, inevitably has limited utility. As the author points out here, the War on Cancer was set up in a way that limits the scope of benefits to health that can result. Prevention is a noble goal, but cancer cannot be entirely (or even largely) prevented by lifestyle choices, as one cannot choose not to age.

50 years of the "war on cancer": lessons for public health and geroscience

Reflecting on the realities of the past 50 years of the "war on cancer", and the reality of the prevalence of comorbidity for populations surviving to the upper limits of the human lifespan, we cannot continue on the same course originally plotted out by the National Cancer Act of 1971. Today cancer is still the second leading cause of death in America. The project of behaviour control has not successfully altered this outcome, in large part because it does not alter the most significant risk factor for cancer - age.

I am not suggesting that public health should concede the battle and abandon the important preventative measures of smoking cessation and a physically active lifestyle. Of course not. But we should have the humility to recognize that doubling down on these efforts for the next half a century is unlikely to yield a significant health dividend for today's ageing populations. Strategic innovation in preventative medicine will be required. The strategy of behaviour control must be supplemented with the strategy of rate control. In order to unify the aspirations to "save people" from cancer mortality while also ensuring they live longer and better lives, the inborn ageing process must also be targeted. To fixate on disease elimination without also aspiring to alter the rate of ageing will prove costly with diminishing health returns because it does not increase the healthspan.

The public health lessons of the 50-year campaign to defeat cancer in the USA ought to inform global public health more generally. The European Commission, for example, has recently identified cancer as a "mission area". A House of Lords "Science and Technology Select Committee" UK report was released, the catalyst of which an assessment of the feasibility of the government's Ageing Society Grand Challenge mission. Chapter 6 of this report is entitled "The Ageing Society Grand Challenge", and it sets the goal of increasing healthy life expectancy by 5 years by 2035. The World Health Organization dedicated the decade 2021-2030 as the decade of "healthy ageing". The campaign identifies four main areas of action-age-friendly environments, combating ageism, integrated care and long-term care. These are all morally laudable, but incomplete, prescriptions.

Like the EU report on defeating cancer, what is missing from the World Health Organization's action plan is undertaking the committed action to develop an applied gerontological intervention to increase the human healthspan. Geroscience is an integral element of public health for today's ageing populations. Redressing the imbalance between the research funding invested in tackling specific chronic diseases vs the most significant risk factor for chronic diseases is critical. The past half a century war on cancer reveals the limitations of continuing on the path of disease elimination for populations that are approaching the upper limits of the human lifespan.

Strategic innovations in preventative medicine are required if we hope to improve the healthspan of today's ageing populations. To make serious headway in cancer prevention, we must target the most significant risk factor - biological ageing. Despite the limits facing behaviour control, there is good reason for optimism that the development of an applied gerontological intervention could help us achieve the important goal of rate control. Age retardation would ensure we improve the quality of life for older people vs simply preventing death by helping older populations manage multi-morbidity.

When President Nixon declared a "war on cancer" nearly 50 years ago, the success of the war was equated with disease elimination. That is a noble but unrealistic goal. Waging a war against an unrealistic goal is harmful for two reasons. Firstly, it means that large investments of public funds are invested into something that is not attainable (of the 200+ types of cancer, none have been cured or eliminated). Secondly, and more importantly, that investment in disease elimination imposed a hefty opportunity cost. Had those same funds been invested elsewhere, for example, targeting the ageing process itself, it could have yielded the population a much more significant health dividend. The primary challenge for today's ageing populations is not to eradicate cancer mortality but rather to increase the human healthspan.

Researchers here propose building a biomarker of aging based on analysis of what they term the volitome, the mix of volatile organic compounds secreted by the body. It is a reasonable suggestion. Near all such profiles of the aggregated output of cellular behavior (such as proteins in blood, or transcript levels in tissue samples) should contain reflections of the state of health and the level of cell and tissue dysfunction associated with aging or disease. Modern machine learning can quickly identify combinations of factors within this class of data that correlate with chronological age - or with biological age, as measured by mortality risk or incidence of age-related disease. The challenge then is to understand how these biomarkers connect to underlying processes of aging, as until that is known, it is hard to use them to assess potential age-slowing or rejuvenation therapies.

Our team and others have proposed a number of potential biomarkers, such as epigenetic clocks, serum N-glycans, and GDF15, associated to aging or age-related diseases. Moreover, during the last years, our group also studied the "volatilome", i.e. a set of endogenous Volatile Organic Compounds (VOCs) resulting from body's metabolism. VOCs are low-weight carbon-based molecules detectable in sweat, exhaled breath, blood, urine, and feces, and that, except for blood, are considered non-invasive diagnostic biomarkers. VOCs are involved in different physiological processes and VOCs profile may differ with age, gender, physiological status, reflecting the metabolic conditions of an individual and represents her/his "odor-fingerprint".

We wondered whether this kind of biomarkers could be useful also to identify people's age, as suggested by previous studies. We then investigated VOCs profile in healthy aging and longevity in humans by analyzing the VOCs in both urine and feces that better mirror the endogenous metabolism of the organism. The samples derived from volunteers of different age, including centenarians and their offspring that represent a sort of "super-controls" to identify potential VOCs biomarkers of successful aging and longevity. We have reported the existence of specific patterns of urinary and fecal VOCs that can discriminate subjects of different age, from young to centenarians, and, even more interesting, centenarians' offspring from age-matched controls.

Among the different VOCs identified in our study, we found that the fecal VOCs belonging to aldehydes class are less abundant in the group of young with respect to the groups of elders, that generally display a greater susceptibility to inflammation and diseases. This finding is in agreement with literature data indicating that metabolites belonging to aldehydes class are produced during inflammatory processes and are involved in several age-related diseases, such as atherosclerosis, cardiovascular diseases, neurodegenerative diseases, and metabolic disorders. These observations suggested that the different VOCs patterns may likely reflect changes in metabolic processes associated with age and health status.

Link: https://doi.org/10.18632/aging.202959

Delivery of recombinant klotho, or fragments of klotho, has been an area of interest for the research community. Upregulation of klotho expression has been shown to extend life in mice, and klotho appears to be involved in regulation of tissue aging in a number of different organs. This may all be the consequence of the effects of klotho on declining kidney function with age, given discoveries to date relating to the relationship between klotho, kidney function, and cognitive aging, but investigations are still ongoing, and other more direct connections may yet be found.

Researchers characterised and compared changes in the structure, function, and gene activity in skeletal muscle across the lifespan in mice. They grouped mice into four age categories - young, middle-aged, old and oldest-old - and looked at muscle weight, type of muscle fibers, whether the muscles had accumulated fat, and skeletal muscle function. Although old mice displayed mild sarcopenia, the common clinical features of sarcopenia were only present in the oldest-old mice. Next, they looked at changes in muscle gene activity and found a progressive disruption in genes known to be associated with the hallmarks of aging from the young to the oldest-old mice.

Next, they looked at whether administering Klotho to mice would have beneficial effects on the muscle healing after injury. They found that applying Klotho after muscle injury reduced scarring and increased structures associated with force production in the animals. Injured mice that received Klotho also had better muscle function - such as muscle twitch and force production - and their whole-body endurance improved two-fold.

Finally, the team looked at whether giving the mice Klotho could reverse age-related declines in muscle quality and function. They found that Klotho administration led to some improvements in the old mice: force production was improved by 17% and endurance when supporting whole body weight was 60% greater compared to mice without treatment. But this was only seen in the old mice, and not in the oldest-old animals. Further investigation showed that Klotho affected genes associated with the hallmarks of aging in all age groups, but that the oldest-old mice showed a dysregulated gene response.

Link: https://elifesciences.org/for-the-press/5f75a126/study-reveals-roadmap-of-muscle-decline-with-age

In today's open access paper, researchers report results that suggest the contribution of B cells, a type of immune cell, to the progression of Alzheimer's disease is meaningful. Approaches to the selective destruction of the B cell complement in mice are fairly well developed, given that it is not harmful in the short term to live without B cells, and the B cell population regenerates quite rapidly when it is depleted. Applying such a method to clear B cells in Alzheimer's mouse models resulted in slowing of progression in the early stages and reversal in the later stages of the condition.

The mechanism of interest here is chronic inflammation in the brain, important to the progression of neurodegenerative conditions. Removing B cells from the picture in some way breaks some of the feedback loops involved in the growing levels of inflammation characteristic of aging and Alzheimer's disease. While the researchers speculate on the details, more work would have to be carried out to pin down exactly what is going on here. B cells are by no means as well studied in the context of Alzheimer's disease as are other types of immune cell, such as microglia.

One interesting point relates to the cells known as age-associated B cells. These age-associated B cells build up with age, as the name might suggest, and are known to be pathological. Trying to remove them has been the motivation for a number of studies of targeted B cell clearance, and removing them does indeed produce benefits in old animals. The researchers here believe that age-associated B cells are not involved in the B cell related contribution inflammation of Alzheimer's disease, however. It is some more general participation of B cells in the state of the aging brain.

Therapeutic B-cell depletion reverses progression of Alzheimer's disease

We provide counterintuitive evidence for a "dark" side of B cells - they exacerbate manifestation of Alzheimer's disease (AD)-like symptoms in addition to producing potentially beneficial amyloid-β plaque-reducing immunoglobulins and expressing AD-ameliorating cytokines. Although the exacerbation in Rag-deficient APP and 5×FAD mice is linked to the loss of protective B cells and T cells, our data revealed that the genetic loss of B cells alone or their transient depletion at the onset of AD improves the disease symptoms of three different mouse models.

Unlike a recent report that linked AD progression to the reduction of anti-inflammatory B1a cells in 5×FAD mice, the numbers of B1a and B1b cells in peripheral blood, spleen, and cervical lymph nodes were either unaffected (in 5×FAD mice even when followed for 4, 7, and 12 months) or upregulated (in 3×TgAD and APP/PS1 mice). However, regardless of their numbers, we recently reported that the function of B1a cells is not static and is rather controlled by the inflammatory milieu. In the aged hosts, B1a cells lose their anti-inflammatory activity and acquire pathogenic functions, such as becoming 4-1BBL+ B1a cells (termed 4BL cells) that induce cytolytic granzyme-B+ CD8+ T cells and promote insulin resistance. In concordance, B1 cells (as well B2 cells, in some models) in AD mice also appeared to acquire an inflamed phenotype, as they upregulated expression of cytokines. Although age-associated B cells also accumulate in aging, we did not detect their involvement in our three types of mice with AD.

Consistent with a recent RNA-seq report that revealed presence of mature B cells in the brains of AD mice, our data indicate that AD increases B cells in the brain, and their IgG in the cortex and hippocampus parenchyma, which was often colocalized with amyloid-β plaques and activated microglia. As in multiple sclerosis and cognitive dysfunction following stroke, B cells in the brain presumably produce immunoglobulins and proinflammatory factors exacerbating AD-promoting neuroinflammation. Our data also indicate that the loss of B cells, thus immunoglobulin G, in the brain significantly retards the development of AD. Although the mechanism of this process is a topic of a different study, we think that brain IgG (or its immune complex) alone or in concert with B-cell cytokines exacerbates neuroinflammation in AD.

One of the biggest challenges in regenerative medicine is ensuring the long-term survival and integration into tissue of any meaningful fraction of transplanted cells. Most transplanted cells simply die. Most early cell therapies achieve benefits via the signaling generated by transplanted cells, in the short period of time before they die. Numerous approaches are under development to try to ensure long-term survival of transplanted cells, but successes have so far been few and far between. Here, researchers report on one of these successes, generating retinal cells that integrate into the retina to produce tissue regeneration.

Researchers have presented the first successful attempt to generate retinal cells that can integrate into the retina. Retinal ganglion cells (RGCs), commonly damaged in glaucoma, are responsible for the transmission of visual information. The scientists managed to not only grow neurons (retinal ganglion cells are considered specialized neurons), but also transplant them into the eyes of mice, achieving the correct ingrowth of artificial retinal tissue. Without treatment, glaucoma can lead to irreversible damage to the optic nerve and, as a result, the loss of part of the visual field. Progression of this disease can lead to complete blindness.

Retinal cells were grown using special organoids, with the tissue formed in a petri dish. These cells were subsequently transplanted into several groups of mice. "Our studies in mice have shed light on some of the basic questions surrounding retina cell replacement, i.e. can donor RGCs survive within diseased host retinas? Or are transplants only possible within young hosts? Using mice in which we used microbeads to artificially elevate intraocular pressure and a model of chemically induced neurotoxicity, we could show that transplanted donor cells survive in disease-like microenvironments. In addition, we could demonstrate that cells survived independent of the donor's age and the location to which the cells were delivered within the retina."

According to the authors, these cells have successfully existed inside mouse retinas for 12 months, which is a significant period for the species. Scientists confirmed that they were able to receive signals from other neurons in the retina; however, the ability of the cells to transmit signals to the brain has yet to be assessed with absolute certainty.

Link: https://mipt.ru/english/news/mipt_and_harvard_researchers_grow_stem_cells_to_cure_glaucoma

An aneurysm is a bulging growth on a blood vessel, at risk of rupture. These can form for a number of reasons, from bacterial infection to age-related weakening of the blood vessel wall. High blood pressure makes the situation worse. An aneurysm of any significant size can cause death or disability when it ruptures. Researchers here note that the inflammatory behavior of macrophage cells appears to be involved in the growth of aneurysms, and targeting a specific gene can adjust that behavior in order to slow aneurysm development in a mouse model of the condition.

A new study investigates a genetic culprit behind abdominal aortic aneurysm, a serious condition that puts people at risk of their aorta rupturing - a potentially deadly event. There are no medications to directly treat the condition and prevent an aneurysm from growing. Current options include things like addressing blood pressure to lower the stress on the arteries and veins running through the body, and making lifestyle changes like quitting smoking. Most people monitor their aneurysm to see if it grows enough to eventually require endovascular or open surgical repair.

For this study, researchers investigated the role of an epigenetic enzyme called JMJD3 in the development of abdominal aortic aneurysm. They found the gene was turned on in both people and mice who had an abdominal aortic aneurysm and that the gene promoted inflammation in monocytes and macrophages. When they blocked the enzyme, it prevented an aneurysm from forming. "Targeting the JMJD3 pathway in a cell specific-manner offers the opportunity to limit abdominal aortic aneurysm progression and rupture."

Link: https://labblog.uofmhealth.org/lab-notes/attacking-aortic-aneurysms-before-they-grow

The years of work that went into investigating the effects of fullerenes (spherical assemblies of carbon molecules, specifically C60 in this case) on life span in rodents are an example of the waste that can occur following the publication of a badly designed study that produces misleading data. The original 2012 study that led to the claim that supplementation with fullerenes dissolved in olive oil increases rat life span was carried out using only a small number of animals and was published in a journal that did not specialize in aging research. This is perhaps because the size of the life span extension claimed was large enough that it would be have been rejected by reviewers familiar with past results. It is too large to be taken at face value without resulting from a much larger and more rigorous study.

Later work showed that fullerenes in oil are in fact quite toxic unless very carefully manufactured, a hurdle requiring some years to pass, and not accounted for at all in the original paper. When tested robustly, using non-toxic formulations, fullerenes in olive oil were found to fail to extend rodent life span. The original study did not control for calorie intake, and so may have been reporting a disguised calorie restriction effect, or simply the result of an artifact of poor study design and execution.

We might then look at today's paper by a different group, in which the authors suggest that the problem is that olive oil on its own is quite harmful to rodent life span, while putting fullerenes into the olive oil counteracts some of these effects. The mechanisms of interest here revolve around oxidation of the lipid molecules in oils, as oxidized and otherwise altered lipids are harmful to cells, versus the sizable antioxidant capacities of fullerenes. At this point there is still at least one next step to conduct, which is to run life span studies based on delivery of water-soluble fullerenes without involving olive oil. This sort of approach has been tested in a preliminary way by a few groups for their ability to assist in control of localized inflammation, but not extensively.

Given the poor performance of systemic antioxidants to date in extending life in animal models, versus benefits for some types of antioxidant shown in inflammatory conditions, I wouldn't expect much to result from this work. The only antioxidant compounds that have produced increased life span are those that specifically target the mitochondria (such as MitoQ, SkQ1, and so forth), and even there the gains in life span in short-lived species are modest at best. These compounds have so far found their greatest success in localized treatment of inflammatory conditions, such as those of the eye.

Effect of long-term treatment with C60 fullerenes on the lifespan and health status of CBA/Ca mice

Several studies claimed C60 fullerenes as a prospective geroprotector drug due to their ability to capture free radicals effectively and caused a profound interest in C60 in life extension communities. Multiple additives are already sold for human consumption despite a small body of evidence supporting the beneficial effects of fullerenes on the lifespan. In order to test the effect of C60 fullerenes on lifespan and healthspan, we administered C60 fullerenes dissolved in virgin olive oil orally to 10-12 months old CBA/Ca mice of both genders for seven months and assessed their survival.

To uncover C60 and virgin olive effects, we established two control groups: mice treated with virgin olive oil and mice treated with drinking water. To measure healthspan, we conducted daily monitoring of health condition and lethality and monthly bodyweight measurements. We also assessed physical activity, glucose metabolism, and hematological parameters every three months.

We did not observe health deterioration in the animals treated with C60 compared with the control groups. Treatment of mice with C60 fullerenes resulted in an increased lifespan of males and females compared with the olive oil-treated animals. The lifespan of C60-treated mice was similar to the mice treated with water. These results suggest that the lifespan-extending effect in C60-treated mice appears due to the protective effect of fullerenes in opposition to the negative effect of olive oil in CBA/Ca mice.

Greater physical activity has been quite comprehensively demonstrated to correlate with reduced mortality in later life. The epidemiological study noted here shows that this relationship also holds up in people who have a higher risk of cardiovascular disease, due to factors such as type 2 diabetes or hypertension. The researchers examined outcomes in patients who improved their level of physical activity between two time points, finding a lower incidence of cardiovascular disease in comparison to those who did not improve. This is consistent with other studies of the role of physical activity in reducing the risk of cardiovascular disease and mortality.

The study included 88,320 individuals from the LifeLines Cohort Study. Participants underwent a physical examination and completed questionnaires about their medical history and lifestyle including exercise. The questionnaires were repeated after approximately four years. Study participants were divided into five groups according to activity levels at baseline and four years: large reduction, moderate reduction, no change, moderate improvement, and large improvement. Participants were followed-up for a median of seven years after the first assessment for the occurrence of cardiovascular disease or death.high cholesterol

A total of 18,502 (21%) individuals had high blood pressure, high cholesterol, and/or diabetes at the start of the study. The average age of this group was 55 years. After adjusting for age, sex, and baseline physical activity, the researchers found that those with a moderate to large improvement in physical activity were around 30% less likely to develop cardiovascular disease or die during follow-up compared to those who did not change their activity level.

The remaining 69,808 (79%) participants did not have high blood pressure, high cholesterol, or diabetes at the start of the study. The average age of this group was 43 years. After adjusting for age, sex, and baseline physical activity, the researchers found that those with large reductions in physical activity had a 40% higher risk of cardiovascular disease or death compared to those who did not change their activity level.

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/Heart-patients-advised-to-move-more-to-avoid-heart-attacks-and-strokes

Governments and large international entities have in many cases published quite expensive and detailed positions on aging. They commonly urge individual and collective action based on the impending collapse of entitlement systems due to changing demographics. The growing number of older people relative to the size of the population as a whole makes pensions, government-run health systems, and the like, increasingly unsustainable in their present form. Something must change. That change must be the development and widespread deployment of therapies to treat the underlying mechanisms of aging, so as to slow and reverse the process of aging. Sadly that is the one approach to the challenge that never appears in these proposals, following the lead of the WHO's 2015 World Report on Aging and Health and 2020 Decade of Healthy Aging, which interventions to slow and reverse aging are not mentioned. The EU Green Paper on Aging discussed here is similarly entirely blind to the role of medical research in the future of aging.

"The Green Paper on Ageing highlights the importance of healthy and active ageing and lifelong learning as the two concepts that can enable a thriving ageing society. Active ageing necessitates promoting healthy lifestyles throughout our lives, including consumption and nutrition patterns, as well as encouraging physical and social activity. Lifelong learning means a constantly acquiring and updating of skills helping people to remain employable and succeed in job transitions."

Active ageing and lifelong learning are important, obvious, and attractive ideas but we would argue that without really addressing the underlying problem of accelerated biological aging and functional decline giving rise to the fundamental problem related to the demographic challenges promoting these ideas alone and proposing them as the remedy is akin to trying to build a house without a foundation.

The three biggest problems of the current Green Paper on Ageing are all rooted in the missed opportunity of learning from and applying the latest biomedical, scientific and technological results. This way the potential effect of this most decisive scientific and technological trend is rendered invisible concerning the changing demographics and hence actually and actively downplaying the role science and technology might play in the long term permanent solution.

1. The Green Paper on Ageing is missing the elephant in the room behind changing demographics affecting Europe (and the world): the real, life-compromising burden of accelerated biological aging in the second half of life, already present in middle age, and reaching its climax in older people.

2. The Green Paper on Ageing appears oblivious to science's current view on the malleability of the biological aging process, and the already mainstream translational geroscience paradigm that offers an interventionist approach to potentially slow, stop, reverse, or rejuvenate these aging processes in order to significantly increase healthy human lifespan.

3. Due to the previous 2 points the Green Paper on Ageing ignores the primary long-term policy solution of the demographic challenge: supporting the focused development and equitable access of science-intensive healthy longevity technologies for all EU citizens.

Link: https://www.longevity.technology/changing-demographics-warrant-solid-longevity-foundation/

Chronic inflammation is a major issue in aging. The immune system reacts inappropriately to rising levels of molecular damage, spurred on by the pro-inflammatory signaling of growing numbers of senescent cells, and enters a state of continual overactivation. This broadly disrupts cell and tissue function throughout the body in many ways. Present approaches to reducing inflammation, largely deployed as treatments of autoimmune conditions, involve the brute force sabotage of important inflammatory signaling pathways such as those involving tumor necrosis factors. This can achieve the goal of reducing chronic inflammation, but at the cost of also sabotaging some of the vital work of the immune system in defending against pathogens and destroying errant cells.

Are there similar brute force approaches that can sabotage immune system signaling pathways that are less involved in vital work and more involved in inappropriate overactivation in old age and autoimmunity? That might be the case. The cGAS-STING pathway is attracting a great deal of research interest of late, and may prove to be a better option than tumor necrosis factor interactions, but it is still involved in the detection of pathogens and problematic cells. A better class of approach might be to instead address the causes of inflammation: the senescent cells, the cell damage, the reasons why the signaling environment shifts to be more inflammatory.

The cGAS-STING pathway as a therapeutic target in inflammatory diseases

The detection of foreign DNA serves as a crucial element of immunity in many organisms. In mammalian cells, this task is contributed in large part by the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which has emerged as a critical mechanism for coupling the sensing of DNA to the induction of powerful innate immune defence programmes. Within this pathway, the binding of cGAS to double-stranded DNA (dsDNA) allosterically activates its catalytic activity and leads to the production of 2′3′ cyclic GMP-AMP (cGAMP), a second messenger molecule and potent agonist of STING.

A salient feature of the cGAS-STING pathway, which sets it apart from several other innate immune signalling mechanisms, is that its activation is triggered by a fundamental element of life (namely DNA) and, therefore, lacks any pathogen-specific attributes. For this reason, cGAS recognizes a broad repertoire of DNA species of both foreign and self origin. Today, our understanding of the diverse functions of the cGAS-STING pathway in host immunity has become clearer, and multiple examples highlight the protective effects of this pathway during infection. Recent studies showing that the cGAS-STING system arose from an ancient bacterial anti-phage mechanism underscore this notion.

Growing evidence has indicated, however, that dysregulation of this highly versatile innate immune sensing system can disrupt cellular and organismal homeostasis by fuelling aberrant innate immune responses associated with a number of pathologies. The parameters that dictate host-protective versus pathogenic activity are still being unfolded, but it appears that the intensity and chronicity of cGAS-STING signalling are major determinants in most cases. In light of this, efforts have been undertaken or are still under way to define strategies that allow selective modulation of cGAS-STING activity in various disease settings.

A critical aspect for the future will be to better understand the minimal level of inhibition required for therapeutic benefit. It is possible that strong reduction of the pathway provokes adverse effects in humans by increasing susceptibility to infection. This may be particularly relevant for the treatment of chronic conditions that require repetitive or continuous treatment regimens. Still, the direct targeting of cGAS-STING bears potential benefits over more non-specific and broadly acting anti-cytokine antibodies or compounds targeting key signalling molecules, such as JAK inhibitors or TBK1 inhibitors, as it leaves intact essential compensatory innate immune recognition pathways, most critically the TLR, RIG-like receptor, and inflammasome pathways.

Researchers here provide evidence to suggest that some of the amyloid-β deposits in the brain that are characteristic of Alzheimer's disease are in fact beneficial and protective, the efforts of immune cells to remove harmful amyloid-β from contact with cells and deposit it in elsewhere. This may or may not help to explain why amyloid clearance therapies have so far failed to produce benefits in patients: it is always hard to say just how large a contribution any one given mechanism has to disease progression. It seems likely that amyloid-β aggregates are either a moderately but not severely harmful side-effect of the real core disease processes - such as chronic infection and its consequences - or that amyloid-β aggregation is only relevant in the early stages of Alzheimer's disease. In the later stages of the condition, a feedback loop of inflammation, cellular senescence, and immune system dysfunction drives the condition.

Alzheimer's disease is a neurological condition that results in memory loss, impairment of thinking, and behavioral changes, which worsen as we age. The disease seems to be caused by abnormal proteins aggregating between brain cells to form the hallmark plaques, which interrupt activity that keeps the cells alive. There are numerous forms of plaque, but the two most prevalent are characterized as "diffuse" and "dense-core." Diffuse plaques are loosely organized, amorphous clouds. Dense-core plaques have a compact center surrounded by a halo. Scientists have generally believed that both types of plaque form spontaneously from excess production of a precursor molecule called amyloid precursor protein (APP).

But, according to a new study, it is actually microglia that form dense-core plaques from diffuse amyloid-beta fibrils, as part of their cellular cleanup. This builds on earlier research showing that when a brain cell dies, a fatty molecule flips from the inside to the outside of the cell, signaling, "I'm dead, eat me." Microglia, via surface proteins called TAM receptors, then engulf, or "eat" the dead cell, with the help of an intermediary molecule called Gas6. Without TAM receptors and Gas6, microglia cannot connect to dead cells and consume them.

The team's current work shows that it's not only dead cells that exhibit the eat-me signal and Gas6: So do the amyloid plaques prevalent in Alzheimer's disease. Using animal models, the researchers were able to demonstrate experimentally for the first time that microglia with TAM receptors eat amyloid plaques via the eat-me signal and Gas6. In mice engineered to lack TAM receptors, the microglia were unable to perform this function.

Digging deeper, they traced the dense-core plaques using live imaging. Much to their surprise, the team discovered that after a microglial cell eats a diffuse plaque, it transfers the engulfed amyloid-beta to a highly acidic compartment and converts it into a highly compacted aggregate that is then transferred to a dense-core plaque. The researchers propose that this is a beneficial mechanism, organizing diffuse into dense-core plaque and clearing the intercellular environment of debris.

"Some people are saying that the relative failure of trials that bust up dense-core plaques refutes the idea that amyloid-beta is a bad thing in the brain. But we argue that amyloid-beta is still clearly a bad thing; it's just that you've got to ask whether dense-core plaques are a bad thing." The researchers suggest that scientists looking for a cure for Alzheimer's should stop trying to focus on breaking up dense-core plaques and start looking at treatments that either reduce the production of amyloid-beta in the first place or therapies that facilitate transport of amyloid-beta out of the brain altogether.

Link: https://www.salk.edu/news-release/in-surprising-twist-some-alzheimers-plaques-may-be-protective-not-destructive/

The inflammatory cytokine TNF is the target of many efforts to find ways to reduce inflammation in conditions characterized by excessive inflammatory activity of the immune system, such as autoimmune diseases. It is a blunt approach, as it reduces not only inappropriate activity, but also the needed activity of the immune system, such as defense against pathogens and destruction of potentially cancerous and senescent cells. The methods of targeting TNF are becoming ever more sophisticated, as this example demonstrates. It is nonetheless the case that better and different classes of treatment will be needed in order to avoid the issue of reducing the capacity of the immune system to carry out necessary tasks.

Researchers describe how novel nanomaterials could assemble into long nanofibers that include a specialized protein, called C3dg. These fibers then were able to activate immune system B-cells to generate antibodies. Due to the protein's ability to interface between different cells in the immune system and activate the creation of antibodies without causing inflammation, researchers have been exploring how C3dg could be used as a vaccine adjuvant, which is a protein that can help boost the immune response to a desired target or pathogen.

In their new nanomaterial, researchers were able put this idea to the test by weaving key fragments of the C3dg protein with epitopes of TNF into nanofibers. The C3dg protein would trigger the B-cells to create antibodies, while the TNF epitopes would provide a blueprint of what the antibodies need to seek out and destroy. "We saw that there was a strong B-cell response, which means there was an increased production of antibodies that targeted TNF. When we delivered the C3dg nanofibers into mice, it was highly protective, and the mice didn't experience an inflammatory response."

When the team tested their nanomaterial in a psoriasis mouse model, they found that the nanofibers carrying C3dg were as effective as a monoclonal antibody therapy targeting TNF. And because C3dg is normally found in the body, it wasn't flushed out of the system by anti-drug antibodies. After examining the psoriasis model, the team made a surprising discovery - C3dg wasn't just stimulating antibody production in the B-cells, it was also influencing the response of T-cells. For their next steps, the team hopes to further explore the mechanisms behind this beneficial T-cell activation. They'll also pursue additional experiments to explore the response to similar nanomaterials in rheumatoid arthritis models.

Link: https://pratt.duke.edu/about/news/self-assembling-nanofibers-prevent-damage-inflammation

Epigenetic clocks assess changing patterns of DNA methylation at CpG sites on the genome that correlate well with chronological age, and to some degree with biological age. People who age more rapidly, as judged by a range of factors such as presence or risk of age-related conditions, tend to have a higher assessed epigenetic age. It remains unclear as to which processes of aging are reflected by any given set of DNA methylation markers, however. For example, the early clocks are insensitive to exercise and fitness. Sedentary people and fit people at any given age tend to measure the same epigenetic age.

Today's open access paper is interesting as a further data point regarding lifestyle interventions for one of the early epigenetic clocks. It involves a small human study using changes in diet, including the use of probiotics, and exercise, which we can probably discount as a meaningful factor given earlier data. The results suggest that diet can make a modest difference of a few years in measured epigenetic age. Unfortunately this still doesn't tell us whether the clock does in fact reflect effects on human life expectancy for this class of lifestyle intervention. The next step on the road to robustly establishing that connection is to calibrate the clock against life span studies in mice using this approach to diet.

Overall, however, this is a taste of what the future holds: every class of intervention clearly and rapidly tested for its ability to affect biological aging. The world in which we can do this is a world in which the best interventions rise to the top of the pile and attract greater investment more rapidly. That is very much needed at the moment: too many resources are devoted to projects in the biology of aging and related medical research and development that cannot possibly produce meaningful gains to healthy human life span.

Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial

Manipulations to slow biological aging and extend healthspan are of interest given the societal and healthcare costs of our aging population. Herein we report on a randomized controlled clinical trial conducted among 43 healthy adult males between the ages of 50-72. The 8-week treatment program included diet, sleep, exercise and relaxation guidance, and supplemental probiotics and phytonutrients. The control group received no intervention.

Genome-wide DNA methylation analysis was conducted on saliva samples and DNAmAge was calculated using the online Horvath DNAmAge clock. The diet and lifestyle treatment was associated with a 3.23 years decrease in DNAmAge compared with controls. DNAmAge of those in the treatment group decreased by an average 1.96 years by the end of the program compared to the same individuals at the beginning with a strong trend towards significance. Changes in blood biomarkers were significant for mean serum 5-methyltetrahydrofolate (+15%) and mean triglycerides (-25%).

To our knowledge, this is the first randomized controlled study to suggest that specific diet and lifestyle interventions may reverse Horvath DNAmAge epigenetic aging in healthy adult males. Larger-scale and longer duration clinical trials are needed to confirm these findings, as well as investigation in other human populations.

Reprogramming cells in order to change their cell type directly has shown some promise in animal studies as a way to generate new neurons in the brain, enabling regeneration. There are many more supporting cells in the brain, various types collectively known as glial cells, than there are neurons. These supporting cells are somewhat more fungible and replaceable, as they are not storing the data of the mind. A gene therapy that turns some small percentage of glial cells into neurons capable of integrating into existing neural circuits could prove to have numerous advantages over the cell therapy approach of growing patient-matched neurons and introducing them into the brain. Logistically, it should be considerable easier, for one. It may also turn out to be more effective, given the challenges inherent in keeping transplanted cells alive for any meaningful length of time following treatment.

Stem cell transplantation has emerged as a promising regenerative therapy for stroke due to its potential for repairing damaged brain structures and improving functional recovery. However, cell transplantation therapies face multiple obstacles including the hosts' immune systems, poor transplanted cell survival, inappropriate migration/homing and differentiation, and the lack of specificity or integration into endogenous brain networks. Some clinical trials have also reported inconsistent results in the efficacy of cell transplantation therapies.

Resident astrocytes in the brain remain mitotic throughout the lifespan and undergo rapid gliosis in response to injury. This characteristic response provides a rich source of cells adjacent to the site of injury. The idea of direct reprogramming of non-neuronal cells allows for the trans-differentiation of glial cells (astrocytes, microglia, and oligodendrocytes) into induced neurons (iNeurons) without passing through a stem cell stage. Theoretically, this is a more efficient way to obtain desirable endogenous neurons from a large cellular pool for "on-site" repair in the brain.

Based on the efficiency and efficacy of glial cell reprogramming, we and others experimented with several combinations of transcription factors and settled on the use of the single neural transcription factor NeuroD1 (ND1). Targeting astrocytes for neuronal reprogramming with different viral vectors has been tested in several animal models of neurodegenerative diseases including ischemic stroke with varying success. The exploration of this approach in animal disease models is at an early stage. The efficacy of neuronal conversion and its contribution to neuronal circuitry repair, the mechanisms involved in the regenerative process, and the functional benefits of this therapy have not been well defined.

Our investigation examined the viability of reprogramming of astrocytes in vitro and in vivo. Reprogramming therapy was tested in a focal ischemic stroke model of rats. After a stroke, we transduced ND1 using a lentivirus vector rather than other viral serotypes such as an adeno-associated virus (AAV) to preserve finer control over the scope of infection to study the mechanics of reprogramming on local circuitry and to limit the therapy to only the injured tissue. Neuronal network repair and functional recovery were confirmed using comprehensive assessments and behavioral tests up to 4 months after stroke. The present investigation presents compelling evidence for the feasibility and effectiveness of utilizing reactive astrocytes as an endogenous cellular source for the generation of neuronal cells to repair damaged brain structures.

Link: https://doi.org/10.3389/fnagi.2021.612856

Researchers here announce the publication of a database of 300,000 single cell transcriptomes across cell types, tissues, and ages in mice. This and similar vaults of data will no doubt keep factions within the research community busy for years to come, refining their efforts to produce useful, verified biomarkers of aging. The most important thing that can be achieved with such biomarkers of aging is the comparatively rapid assessment of different approaches to rejuvenation. At present all too much of the field is focused on projects that cannot possible do all that much good in terms of lengthening healthy life span. Redirecting researchers to better approaches much earlier in the development process is a desirable outcome.

Aging leads to the decline of major organs and is the main risk factor for many diseases, including cancer, cardiovascular and neurodegenerative diseases. While previous studies have highlighted different hallmarks of the aging process, the underlying molecular and cellular mechanisms remain unclear. To gain a better understanding of these mechanisms, the Tabula Muris Consortium created the single-cell transcriptomic dataset, called Tabula Muris Senis (TMS). The TMS contains over 300,000 annotated cells from 23 tissues and organs of male and female mice. "These cells were collected from mice of diverse ages, making the data a tremendous opportunity to study the genetic basis of aging across different tissues and cell types."

The original TMS study mainly explored the cell-centric effects of aging, aiming to characterise changes in the composition of cell types within different tissues. In the current gene-centric study, researchers focused on changes in gene expression that occur during the aging process across different cell types. Using the TMS data, they identified aging-dependent genes in 76 cell types from 23 tissues. They then characterised the aging behaviours of these genes that were both shared among all cell types ('globally') and specific to different tissue cells.

"We found that the cell-centric and gene-centric perspectives of the previous and current studies are complementary, as gene expression can change within the same cell type during aging, even if the composition of cells in the tissue does not vary over time. The identification of many shared aging genes suggests that there is a coordinated global aging behaviour in mice." The team then used this coordinated activity to develop a single-cell aging score based on the global aging genes. This new high-resolution aging score revealed that different tissue-cell types in the same animal can have a different aging status, shedding light on the diverse aging process across different types of cells.

Link: https://elifesciences.org/for-the-press/f0e7a8d9/researchers-reveal-aging-signatures-across-diverse-tissue-cells-in-mice

Stem cell activity declines with age for a variety of reasons. Damage in the stem cells, damage in the supporting cells of the stem cell niche, as well as altered behavior in stem cells and niche cells, a reaction to signaling changes such as increased inflammation. In some populations, such as muscle stem cells, the evidence suggests that reactions to signaling are a much more important factor than intrinsic damage. Those stem cells can in principle be put back to work in an aged individual. For hematopoietic stem cells, responsible for generating blood and the immune system, the evidence is less clear. In very late life it has been shown that these cells are very damaged, but it remains to be determined as to whether the majority of the problem is damage or reactions to signaling in earlier old age.

Given this, more research such as the work noted here is needed to better understand the aging of this vital stem cell population and its niche. The nature of this age-related decline determines which approaches to rejuvenation are more likely to work. The data here suggest that delivering new, replacement hematopoietic stem cells will be impeded by changes and damage in the aged stem cell niche. The niche is a sufficiently important determinant of function to require attention.

Aged bone marrow niche impedes function of rejuvenated hematopoietic stem cells

A new study shows that the youthful function of rejuvenated HSCs upon transplantation depends in part on a young bone marrow "niche," which is the microenvironment surrounding stem cells that interacts with them to regulate their fate. "The information revealed by our study tells us that the influence of this niche needs to be considered in approaches to rejuvenate old HSCs for treating aging-associated leukemia or immune remodeling."

Old HSCs exhibit a reduced reconstitution potential and other negative aspects such as altered gene expression profiles and an increase in a polar distribution of proteins. (Polarity is believed to be particularly important to fate decisions on stem cell division and for maintaining an HSC's interaction with its niche. Consequently, a failure to establish or regulate stem cell polarity might result in disease or tissue deterioration.) Aging of HSCs might even affect lifespan. Researchers already knew that increased activity of a protein called Cdc42, which controls cell division, leads to HSC aging, and that when old HSCs are treated ex vivo with CASIN, an inhibitor of Cdc42 activity, they stay rejuvenated upon transplantation into young recipients. The aim of this latest study was to learn what happens to these rejuvenated HSCs when they are transplanted into an aged niche.

Researchers transplanted rejuvenated aged HSCs into three groups of mice: young (8 to 10 weeks old), old (19 to 24 months old) and young cytokine osteopontin (OPN) knockout mice (8 to 12 weeks old). The team had recently demonstrated that a decrease in the level of secreted OPN in the aged bone marrow niche confers hallmarks of aging on young HSCs, and also that secreted OPN regulates HSC polarity. Old HSC and rejuvenated old HSCs were therefore transplanted into the OPN knockout recipients to test whether a lack of this protein in the niche affects the function of old rejuvenated HSCs. The results were then analyzed for up to 23 weeks after transplantation."They showed us that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of OPN found in aged niches. This tells us that in order to sustain the function of rejuvenated aged HSCs, we will likely need to address the influence of an aged niche on rejuvenated HSCs."

An aged bone marrow niche restrains rejuvenated hematopoietic stem cells

Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs.

The raised blood pressure of hypertension is well known to accelerate the progression of atherosclerosis. It certainly makes it more likely for blood vessels weakened by atherosclerotic lesions to rupture, or for the lesions themselves to fragment and cause blockages. Beyond that, however, mechanisms are at work in the environment of high blood pressure to accelerate the growth of these lesions. The major consequences of atherosclerosis, stroke and heart attack, are the cause of death for a sizable fraction of all people, and this is why blood pressure control produces a meaningful reduction in mortality risk, by slowing the progression towards those consequences.

Blood pressure-lowering drugs are routinely used to prevent the development of atherosclerosis and heart disease, but the mechanism of this effect is still unknown. People suffering from high blood pressure (hypertension) often have accompanying changes in the hormones that control blood pressure and it has been unclear whether the pressure itself or the hormonal changes are the driver of accelerated atherosclerosis. To investigate this, researchers analyzed the development of atherosclerosis in minipigs that were genetically engineered to have high blood cholesterol and develop atherosclerosis.

Minipigs have arteries that are very similar in structure to human arteries and like humans they develop atherosclerosis in the heart when exposed to high blood cholesterol. By manipulating blood pressure in the pigs and by analyzing the effects on arteries in the heart, the researchers found that the direct forces of pressure on arteries leads to structural changes that facilitate the development of atherosclerosis. "Arteries become denser and allow less passage of molecules from the blood. This includes the LDL particles that carry blood cholesterol, which instead accumulate in the innermost layer of arteries, where they drive the development of atherosclerosis."

This finding uncovers an intimate relationship between the most important risk factors for atherosclerosis, LDL cholesterol and high blood pressure. While it has been known for decades that accumulation of LDL particles in arteries lead to atherosclerosis, the new research shows that high blood pressure accelerates the accumulation of LDL. Therefore, high blood pressure aggravates the effect of having high LDL cholesterol in the blood.

Link: https://www.cnic.es/en/noticias/jacc-cnic-researchers-explain-how-high-blood-pressure-most-important-cause-disease

Researchers here provide evidence suggesting that one of the mechanisms by which senescent cells encourage nearby cells to also become senescent is via recruitment of neutrophil cells, a somewhat more complicated process than the direct signaling investigated to date. In its role as a suppressor of cancer, it makes sense for the state of cellular senescence to be transmissible to nearby cells, as that raises the chances of successfully preventing cancer from arising in a localized environment of cell damage. In aging, it makes things worse, however. Excessive numbers of lingering senescent cells cause harm to their surroundings and make that harm worse over time via the creation of yet more senescent cells.

The immune system is a collection of cells and proteins that works to keep the body healthy. But it's a balancing act. Tip in one direction and an infection might cause organ damage or lead to sepsis. Overbalance in the other and the cure might lead to an autoimmune disease. Neutrophils are a key part of immune system action. They help healing by clearing out cellular debris after an infection. They're also armed and can kill microbes. During infection, neutrophils release a short blast of unstable molecules called reactive oxygen species.

Another way the immune system keeps the body healthy is by telling damaged cells to perish. But not all cells die. Cells told to close down by the body sometime ignore that signal. Instead, they live in a sort of zombie state, undead but spewing toxic chemicals. These cells are senescent cells. They damage their neighbors through release of a toxic protein stew.

Researchers examined neutrophils' effect on human and mouse cell senescence. They co-cultured neutrophils with human cells and depleted neutrophils in mice to determine their role in encouraging senescence. "We asked if neutrophils could be drivers of cellular senescence in tissues and contribute to aging. We found that neutrophils can cause senescence in neighboring non-immune cells by damaging their telomeres via reactive oxygen species. We also found that if we deplete neutrophils in mice, we can prevent telomere damage and senescence. Our study suggests an evolutionary trade-off between having a good working immune system and age-related pathology. While neutrophils have evolved to play important roles in fighting infection, they may contribute to collateral damage and induction of cellular senescence which will be detrimental later in life."

Link: https://discoverysedge.mayo.edu/2021/03/25/balancing-damage-and-protection-neutrophils-may-lead-to-cell-aging/

Calorie restriction and intermittent fasting have been extensively studied in the context of aging, and most of the age-slowing interventions so far tested in animal studies are derived in some way from a knowledge of the stress response mechanisms triggered by a lowered calorie intake. The long term effects of calorie restriction and fasting in short-lived species are quite different from those in long-lived species: only the short-lived species exhibit a meaningful extension of life span, as much as 40% in mice. Yet the short-term effects on metabolism and cellular mechanisms are very similar. The beneficial response to periods of low nutrient availability evolved very early in the development of life, likely because it increases the chance of living to replicate in the next period of abundance.

The short-term effects of calorie restriction are beneficial to normal cells, but harmful to cancer cells. Calorie restriction upregulates cell maintenance mechanisms likely to cause cancer cells to self-destruct. This is now well known, demonstrated in animal models and human trials. In recent years researchers have put considerable effort into codifying and quantifying fasting and fasting mimicking diets in the context of cancer treatment. Similarly, there is considerable interest in the application to cancer treatment of calorie restriction mimetic drugs, those that induce some fraction of the response to lowered calorie intake. An example is the class of mTOR inhibitors, known to slow aging and lower cancer incidence in mice.

Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy

Fasting and caloric restriction (CR) were shown in non-human primates to reduce the incidence of not only cancer but also metabolic diseases, arteriosclerosis, and neurodegeneration - thus extending the healthspan. Furthermore, fasting and CR were shown in yeast, plants, worms, flies, and rodents to prolong lifespan and reduce the incidence of a wide array of age-associated pathologies, notably malignant diseases. Fasting-mimicking-diets (FMDs) reproduce the effects of fasting while maintaining a food supply, yet with a limited number of calories and a particular macronutrient composition, frequently poor in proteins, enriched in unsaturated fats, and with low to moderate proportions of carbohydrates. FMDs were shown in pilot trials to reduce risk factors associated with aging, diabetes, cardiovascular disease, and cancer, without major adverse effects. In this review, when indistinctively referring to fasting, CR, and/or their mimetics, we will use the term "energy reduction" (ER).

It has been known for more than a decade that starvation protects normal but not transformed cells against chemotherapeutics and oxidative damage, in yeasts, cell cultures, and mice. This effect has been observed in several malignancies such as colon carcinomas, melanomas, gliomas, and breast cancers. Such phenomenon has been dubbed "differential stress resistance" (DSR; sometimes referred to as "differential stress sensitization"). DSR likely originates from the independence of malignant cells from growth signals and their insensitivity to anti-growth signals. These characteristics result from oncogenic gain-of-function mutations affecting the activity of AKT, mechanistic target of rapamycin (mTOR), RAS, and other pro-proliferative signaling factors, and/or of loss-of-function mutations in genes encoding tumor suppressors such as TP53. Consequently, cancer cells are unable to adapt to the lack of nutrients and maintain a sustained proliferation. On the contrary, normal cells switch to a maintenance program conferring resistance to stress.

One of the knock-on effects of ER is autophagy induction, which is triggered in response to cellular stress such as DNA damage, endoplasmic reticulum or mitochondrial stress, oxidative or metabolic stress. In cancer cells, autophagic activity helps to survive in the hypoxic and nutrient-deprived tumor microenvironment and has also been described as a drug resistance mechanism. Somewhat counter-intuitively, this knock-on autophagy induction is not detrimental to the general antitumoral effect of ER and helps explain DSR. As we have seen, cancer cells are more sensitive to metabolic stresses and, as we know, they are also more sensitive to genotoxic stress than most somatic cells. Thus, the concomitant amplification of these two stresses thanks to ER and chemotherapy can prove fatal to malignant cells, whereas ER-induced autophagy probably contributes to its observed protective effect against chemotherapy in healthy cells.

DSR is thus mediated in part by the different metabolic requirements of cancer and healthy cells, but also - and perhaps chiefly - by the cellular effects of ER, especially as it pertains to autophagy. We have known for a few years that autophagy promotes (i) cancer cell immunogenicity, (ii) tumor-bed immune infiltration, and (iii) depletion of tumor-infiltrating regulatory T cells, especially when autophagy is induced at the same time as immunogenic cell death (ICD)-inducing agents are administered. This points towards an immune mechanism that explains the capacity of ER to prevent - and probably even to treat - cancer. This has led us and others to propose ER as an adjuvant to immunotherapy, especially as ER is relatively well tolerated.

Alzheimer's disease is characterized by the aggregation of first amyloid-β and then tau protein in later stages. It took many years and many attempts to produce immunotherapies capable of clearing amyloid-β from the brain, only to find that this doesn't in fact help patients to any great degree. Amyloid-β may be a side-effect of the causative mechanisms - such as infection, or chronic inflammation - or only important in the earliest stages of the development of Alzheimer's. By the time tau aggregation happens, a different disease process has become dominant. One of the next options is to target tau protein with the same sorts of immunotherapy technologies. So far this is proceeding in much the same way, with the first attempts failing to achieve meaningful levels of clearance.

With anti-amyloid antibodies now consistently hitting their target, tau immunotherapy represents the next frontier. In Alzheimer's disease, tau tangles correlate far more closely with cognitive decline than plaques do, and tau aggregates are the main pathology in many related disorders. As with amyloid, however, initial trials of anti-tau antibodies have been beset by failures. Already, several antibodies that bind the N-terminus or C-terminus of tau have been scuttled after not doing recipients any good. Meanwhile, preclinical evidence suggests that antibodies that go after the protein's mid-section, particularly its microtubule-binding region (MTBR), may be better at preventing aggregates from spreading. Several such antibodies have now entered Phase 1 or 2.

At the 15th International Conference on Alzheimer's and Parkinson's Diseases, researchers discussed a number of these programs. Roche offered a first look at biomarker data from the negative Phase 2 trial of the N-terminal-targeting antibody semorinemab. Other speakers touted MTBR-binding antibodies. Pinteon Therapeutics showed preliminary Phase 1 findings for PNT001, while the Technical University of Munich presented on UCB's beprenemab, also in Phase 1. Prothena's MTBR-binder PRX005 is still preclinical, but the company offered mechanistic data on how it might inhibit the transfer of pathological tau.

Time will tell if this newest crop can perform in the clinic. Researchers believe the field is making progress in figuring out how to target the protein, and are encouraged by cerebrospinal fluid data that link cerebrospinal fluid MTBR tau with tangles, and specific tau phospho-species with plaques. "That's really exciting for us as a field. We're learning so much more about this target."

Link: https://www.alzforum.org/news/conference-coverage/n-terminal-tau-antibodies-fade-mid-domain-ones-push-fore

There has been some evidence for the oral microbiome, particularly the harmful bacterial species responsible for gingivitis, to contribute to systemic inflammation throughout the body. This in turn raises the risk of suffering from dementia, including Alzheimer's disease. The mechanisms look plausible, but the epidemiological evidence is mixed, suggesting that this is a small contribution to overall risk. Alzheimer's is a condition characterized by a long slow buildup of amyloid, and a later and more damaging aggregation of tau protein. Researchers here find that the presence of harmful microbial species in the oral microbiome correlates with a measure of amyloid aggregation, but not with tau aggregation in older patients. This suggests perhaps a contribution to the early establishment of the condition, but not to its later progression.

Alzheimer's disease is characterized by two hallmark proteins in the brain: amyloid beta, which clumps together to form plaques and is believed to be the first protein deposited in the brain as Alzheimer's develops, and tau, which builds up in nerve cells and forms tangles. "The mechanisms by which levels of brain amyloid accumulate and are associated with Alzheimer's pathology are complex and only partially understood. The present study adds support to the understanding that proinflammatory diseases disrupt the clearance of amyloid from the brain, as retention of amyloid in the brain can be estimated from cerebrospinal fluid (CSF) levels. Amyloid changes are often observed decades before tau pathology or the symptoms of Alzheimer's disease are detected."

The researchers studied 48 healthy, cognitively normal adults ages 65 and older. Participants underwent oral examinations to collect bacterial samples from under the gumline, and lumbar puncture was used to obtain CSF in order to determine the levels of amyloid beta and tau. To estimate the brain's expression of Alzheimer's proteins, the researchers looked for lower levels of amyloid beta (which translate to higher brain amyloid levels) and higher levels of tau (which reflect higher brain tangle accumulations) in the CSF.

Analyzing the bacterial DNA of the samples taken from beneath the gumline,the researchers quantified bacteria known to be harmful to oral health (e.g. Prevotella, Porphyromonas, Fretibacterium) and pro-oral health bacteria (e.g. Corynebacterium, Actinomyces, Capnocytophaga). The results showed that individuals with an imbalance in bacteria, with a ratio favoring harmful to healthy bacteria, were more likely to have the Alzheimer's signature of reduced CSF amyloid levels, indicating low clearance and greater amyloid in brain tissue. The researchers hypothesize that because high levels of healthy bacteria help maintain bacterial balance and decrease inflammation, they may be protective against Alzheimer's. The researchers did not find an association between gum bacteria and tau levels in this study, so it remains unknown whether tau lesions will develop later or if the subjects will develop the symptoms of Alzheimer's.

Link: https://www.eurekalert.org/pub_releases/2021-04/nyu-iig040721.php

Today's open access commentary is, I think, an overreaction to present challenges in engineering greater longevity via metabolic manipulation. I would be the first to say that altering the operation of metabolism is not a good path forward, at least if the goal is to engineer greater healthy longevity in our species. Cellular metabolism and its intersection with aging is ferociously complex and poorly understood in detail. Those details matter greatly: there are many feedback loops and switches based on protein levels that will change from beneficial to harmful for reasons that only become apparent after years of painstaking research. The best-studied mechanisms that link cellular metabolism to individual and species longevity have been under investigation for decades, and are still at a point at which related interventions are haphazardly beneficial and poorly understood.

Further, those best studied mechanisms, linked to the response to calorie restriction and other stresses, cannot greatly increase life span in long-lived species. They work quite well in short-lived species. That is well demonstrated: calorie restriction itself boosts mouse life span by as much as 40%, and certainly does not do that in humans. Thus we should not be looking to altered metabolism as a path that can add decades to the healthy human life span in the foreseeable future.

Arguing that this line of development is hard, and that all of the specific approaches examined so far appear to be capable of producing only low yields at best, in terms of healthy years added, is one thing. Arguing that it is impossible to ever achieve meaningful gains via this line of development is quite another. It is ridiculous to argue that it is impossible in principle to engineer humans to be very long-lived by changing the operation of cellular metabolism. We only have to look at the wide range of life spans in mammals to note that some concrete collection of differences must be enabling naked mole-rats to live nine times as long as mice, or for whales to live for centuries. Making significantly longer-lived humans through the approach of altered cellular metabolism is scientifically plausible - it just isn't a viable project at this time, and probably won't be for a lifetime yet.

This is why many people who have looked into the field in detail support the damage repair approach to rejuvenation, as first put forward by Aubrey de Grey and presently championed by the SENS Research Foundation and its network of allies and researchers. This is explicitly a strategy to work around the inability to make near term progress in altering metabolism. Instead we keep the metabolism we have, and target the periodic elimination of the various well-described forms of cell and tissue damage that cause aging. Remove the damage, and rejuvenation results, as illustrated in animal studies in which senescent cells are selectively destroyed via senolytic therapies.

The Zugzwang Hypothesis: Why Human Lifespan Cannot Be Increased

Lifespan is one of the most variable life history traits in the animal kingdom, lasting from days to centuries. Despite intensive investigation, there are still many grey areas in our understanding of the factors which contribute to the variability of lifespan. Humans are among the fortunate animals which have an unusually long lifespan compared to their similar sized mammals. On the flip side, the long lifespan of humans and large genetic heterogeneity are important reasons why it is very difficult to use humans as models to study ageing or longevity or test the efficacy of anti-ageing interventions. Ageing studies on humans often require a very large cohort of people and can potentially be affected by many confounding factors. As a consequence, most studies involving ageing, lifespan, and anti-ageing interventions are based on model systems.

In the evolutionary history after divergence from the great apes, the most recent of our primate ancestors, humans have completed almost 300,000 generations. During this period, the lifespan of H. sapiens has almost doubled. The increased longevity of humans is, in part, attributable to environmental changes; improved food, water, and hygiene; reduced impact of infectious disease; and improved medical care at all ages. However, the above factors had an opportunity to play some role in increasing lifespan only in the last 2 centuries. The dramatic increase in human lifespan compared to our nearest ancestors, should, therefore, must have other valid explanations. It is highly conceivable that forces of natural selection may have played vital role in increasing the basic longevity of humans.

Zugzwang is a German word with the literal meaning "compulsion to move." This word is frequently used in chess to describe a situation when a player gets a disadvantage because it is his turn to play, but all the available moves are bad. In Zugzwang position, any move the player makes will clearly weaken his position. Here, I propose that at this stage of evolution, humans may face the Zugzwang problem. Scientific research and the understanding of the hallmarks of ageing now provide humans with more than a dream to extend lifespan. However, it must be taken into consideration that natural selection has already played its part in extending human lifespan much beyond the expectation. All possible mechanisms which can increase longevity in lower animals have already been exploited by natural selection to stretch human lifespan. Any artificial attempt to tinker, through any possible intervention, with the signalling pathways or transcription factors to achieve a longer lifespan may actually be disadvantageous to humans.

Humans may thus be considered to be in the Zugzwang state. Humans may have already achieved or approached the maximum life­span, and further lifespan extension may be very difficult or impossible. Documented record of human longevity for the last 100 years (with a conservative estimate of data from 8 billion individuals) shows that the limit of human lifespan is around 122 years; the fact that no individual has lived beyond this limit is a clue to the validity of the Zugzwang hypothesis.

The results of this epidemiological study suggest that suffering from untreated sleep apnea can raise the risk of later dementia and mild cognitive impairment by 20-30%. How the repeated hypoxia in the brain produced by sleep apnea results in a raised risk of dementia isn't understood in detail, but it has been shown to lead to structural changes in brain regions connected to memory. It is also possible that the correlation of obesity with sleep apnea muddies the waters, and that sleep apnea isn't actually the primary issue, given the harms dcaused by excess visceral fat tissue. That makes the data here interesting, in that it compares treated and untreated patients exhibiting sleep apnea, and finds a meaningful difference.

To examine associations between positive airway pressure (PAP) therapy, adherence, and incident diagnoses of Alzheimer's disease (AD), mild cognitive impairment (MCI), and dementia not-otherwise-specified (DNOS) in older adults, this retrospective study utilized Medicare data of 53,321 beneficiaries, aged 65+, with an obstructive sleep apnea (OSA) diagnosis prior to 2011.

Study participants were evaluated using ICD-9 codes for neurocognitive syndromes [AD(n=1,057), DNOS(n=378), and MCI(n=443)] that were newly-identified between 2011-2013. PAP treatment was defined as presence of ≥1 durable medical equipment (HCPCS) code for PAP supplies. PAP adherence was defined as ≥2 HCPCS codes for PAP equipment, separated by ≥1 month. Logistic regression models, adjusted for demographic and health characteristics, were used to estimate associations between PAP treatment or adherence and new AD, DNOS, and MCI diagnoses.

In this sample of Medicare beneficiaries with OSA, the majority (78%) of beneficiaries with OSA were prescribed PAP (treated), and 74% showed evidence of adherent PAP use. In adjusted models, PAP treatment was associated with lower odds of incident diagnoses of AD and DNOS (odds ratio 0.78). Lower odds of MCI, approaching statistical significance, were also observed among PAP users (odds ratio 0.82). PAP adherence was associated with lower odds of incident diagnoses of AD (odds ratio 0.65). In conclusion, airway pressure treatment and adherence are independently associated with lower odds of incident AD diagnoses in older adults. Results suggest that treatment of OSA may reduce risk of subsequent dementia.

Link: https://doi.org/10.1093/sleep/zsab076

Here find supporting evidence for the SENS view of lipofuscin and lysosomal dysfunction in aging. Lysosomes are the recycling units of the cell, packed with enzymes to break down unwanted structures and molecules into raw materials. Over time, long-lived cells such as the neurons of the central nervous system are negatively affected by the build up of resilient metabolic waste that is challenging to break down. Collectively this waste is called lipofuscin, but it contains many different problem compounds, and overall is poorly catalogued. Lysosomes in old neurons are observed to be bloated and dysfunctional, leading to cells that become overtaken with broken machinery that cannot be recycled. As noted here, the end result is cell death, and an accelerated pace of neural cell death is the road to neurodegenerative conditions.

A toxic brew of lysosomal lipids, reactive iron atoms, and oxidative stress can spell doom for human neurons. This is the upshot of the first-ever CRISPR screens at the genome-wide level in these cells. Researchers used the genome-editing tool to dial up or down expression of each protein-coding gene in the human neuronal genome. They uncovered a surprising connection between endolysosomal processing and the iron-dependent cell-death pathway called ferroptosis.

Zeroing in on that pathway, the researchers found that in the absence of the lysosomal protein prosaposin (PSAP), glycosphingolipids accumulate in the lysosomes, setting off oxidative stress. This results in a toxic mesh of ferrous ions and peroxidized lipids that can kill neurons via the ferroptosis pathway. The findings connect pathways that have been implicated separately in neurodegenerative disease, and support the idea that iron-rich "aging pigments" of lipofuscin, commonly spotted in older brains, might not be so benign after all.

What is the connection between PSAP and ferroptosis? Examining PSAP knockout neurons, the researchers found that the lysosomes were dramatically enlarged, and chock-full of glycosphingolipids. Strikingly, they found that these lipid-logged organelles were also electron-dense, suggesting they were loaded with iron. In fact, these densities bore an uncanny resemblance to lipid-iron granules called lipofuscin, also known as aging pigment. Lipofuscin soaks up the metal ions from the detritus of iron-rich organelles such as mitochondria, and this iron is thought to provoke the production of reactive oxygen species via the Fenton reaction.

Could this cascade play out in the aging brain? All of the culprits are there. For one, oxidative stress is known to rise in the brain with age, and lysosomal function also flags. Levels of not only lipofuscin, but also reactive iron increase in aging brains and even more so in neurodegenerative disease.

Link: https://www.alzforum.org/news/research-news/dysfunctional-lysosomes-cause-ferroptosis-neurons

MRBL is one of the many projects relevant to the treatment of aging that is in George Church's orbit. This is a collection of gene therapy technologies intended for delivery of vectors to areas of skin directly, coupled with analysis of age-related and disease-related gene expression changes in skin cell populations to provide targets. It is a viewed as a basis for approaches in cell reprogramming that could make aged skin cells behave in a more youthful fashion, overriding their response to the age-damaged local environment.

In terms of mechanisms known to be of interest in aging, upregulation of collagen production is an obvious goal, generally agreed upon to be beneficial if achieved. A more interesting but more challenging result to aim for would be the deposition of elastin in a structurally correct manner. Beyond these two, there are many other more subtle issues in cell misbehavior related to the aging of skin, from stem cell activity to coordination of wound healing in the dermis and epidermis.

That said, it isn't clear that forcing more a youthful behavior in cells via gene therapies is the best way forward in all matters relating to aging. It neglects root causes in favor of trying to override them selectively, allowing those root causes to continue to produce all of their other consequences. Chronic inflammation, for example, has a broadly negative impact on tissue function in skin, as is also the case in other organs. Clearing senescent cells, and removing other causes of systemic inflammation, are likely better approaches than trying to force cells to perform correctly, one gene at a time, in an inflamed environment.

MRBL: Next-Generation Gene Therapy for Molecular Skin Rejuvenation

The skin is the largest organ in the body, and carries out multiple vital functions, including protective barrier functions against the loss of moisture and mechanical, UV, and other injuries, immune defense functions, as well as sensory functions. For maintaining its integrity and multifaceted performances, skin relies on a range of different cell types that compose and support its layered organization, each expressing specific molecules that together facilitate physical cell interactions and communication between them, as well as specialized functions.

The gradual decline in the production of many of those molecules is associated with the natural aging process of skin. Separately, a plethora of skin diseases are driven by mutations in single genes that can strike much earlier in life. In both cases, targeted therapeutics that could slow skin aging and directly interfere with the disease pathology of monogenic skin diseases are not available. Commonly applied treatments are merely palliative, reducing the severity symptoms or simply masking the visible damage caused to the skin without actually addressing the condition.

To overcome the lack of truly curative and targeted treatments, a multidisciplinary team has developed a comprehensive gene therapy platform that combines a new computational target discovery platform with improved skin cell-specific adenovirus-associated virus (AAV) gene delivery vehicles, and a novel biomaterials-mediated local delivery of the genetic payloads to affected areas of the skin. Strategically targeting both disease (short-term) and aging (long-term), this next generation skin gene therapy platform builds on the insight that the pathology of genetic diseases often recapitulates specific age-related degenerations.

Fortuitously, researchers found that key targets in aging biology could be leveraged as therapeutics for monogenic diseases, as the genes affected in such diseases were also powerful determinants of the aging process. Using their new-found understanding of aging dynamics, the team has built a time-resolved genetic network of skin aging, and is currently validating novel age-driving genetic targets identified from the resulting map in cell and animal studies.

Denitsa Milanova on MRBL - Gene Therapy for Skin Rejuvenation

I'm working on an Institute Project called MRBL, which essentially enables in situ genetic engineering of the skin. It's a platform technology and has a variety of applications. We started the project looking at the hardest problem - how to solve skin aging at the molecular level. Our gene-potentiating technology could make skin cells go back to their younger state, causing a true rejuvenating effect, and we're trying to get there by modifying the levels of the right fingerprint of genes in the skin.

This technology can also be applied to monogenetic skin diseases, which are diseases that are controlled by the malfunction of a single gene. These conditions manifest in phenotypes like blistering skin and numerous open wounds. With MRBL we are creating novel therapeutics that can correct the levels of such dysfunctional genes or even permanently correct mutations causing injured skin using a skin cell-specific, minimally invasive, adenovirus-associated (AAV)-based gene delivery system.

Beyond that, we are using the same technology to try and leverage the skin as a bioreactor for the production of neutralizing antibodies directly in the body that could help fight HIV, COVID-19 or other infectious diseases. In these instances, the skin is not being treated because it is sick or aging, but instead used as a "factory" to produce therapeutic antibodies or even foreign proteins that stimulate the immune system in a protective way.

Yuva Biosciences is attempting to treat skin aging by improving mitochondrial function, and they are taking a cosmeceutical approach. It is far faster and less costly to bring treatments to market via the cosmetics regulatory pathway than via the Investigational New Drug pathway. One has to accept considerable restrictions over what sort of approaches can be used, meaning that one is largely constrained to using combinations of known compounds, taken from a list of those that have been well characterized already. This in turn means that effect sizes tend not to be large.

Historically this has been an industry in which profit is driven by marketing rather than efficacy, so developers have not been all that incentivized to produce products that worked. Targeting the mechanisms of aging will gradually introduce some degree of efficacy into this field, however. Or at least we can hope that this will be the case. We can look at the reduction of cellular senescence in skin following months of topical low dose rapamycin treatment, for example, or the conceptually similar but technically different OneSkin approach to topical senotherapeutics.

With an initial focus on developing cosmeceuticals, US start-up Yuva Biosciences aims to harness mitochondrial science to address skin aging and age-related hair loss. The company has developed a natural topical treatment, imminently about to enter human trials, which it hopes will demonstrate an ability to promote hair growth and reduce skin wrinkles.

During founder Keshav Singh's work to explore whether mice induced with mitochondrial dysfunction were more likely to develop cancer, he came across a surprising result. "The first thing we noticed was that, within four weeks or six weeks, these mice developed skin wrinkles, and lost hair. When we restored the mitochondrial function, the hair grew back. So that gave us a direct link between mitochondrial dysfunction and hair loss and skin aging." The results convinced Singh that he should try to discover a compound that would drive similar results and set about testing a range of natural and pharmaceutical products.

"We derived fibroblast cells from these mice, and did a very targeted screening. And, lo and behold, within a month we found a natural compound that can prevent skin wrinkles and hair loss in mice. So we started Yuva Biosciences and have started work towards commercialising both the initial compound discovered, plus a pipeline of compounds, with a focus on natural compounds, because those can go to market as cosmeceuticals. We're actually starting human trials, and we'll be conducting three trials over the next couple months - two for skin, one for hair. And so that'll provide a lot of exciting results and hopefully some exciting products."

Link: https://longevity.technology/targeting-mitochondria-to-beat-hair-loss-and-skin-wrinkles/

The decline of the immune system is of great importance in aging. Vulnerability to infection, a decreased surveillance of senescent cells and cancerous cells, and growing chronic inflammation all take their toll. A sizable fraction of this problem stems from the diminished supply of new T cells of the adaptive immune system. T cells begin life as thymocytes in the bone marrow, then migrate to the thymus where they mature. Unfortunately, the thymus atrophies with age, a process known as thymic involution, in which active tissue is replaced by fat. The T cell supply falters, and as a result the existing T cell population becomes ever more damaged and dysfunctional. Researchers have shown that raised cancer risk over time maps very well to the pace of thymic involution, and here more data is deployed to point out the same correlation for vulnerability to infectious disease.

Here we report that COVID-19 hospitalisation rates follow an exponential relationship with age, increasing by 4.5% per year of life. This mirrors the exponential decline of thymus volume and T-cell production (decreasing by 4.5% per year). COVID-19 can therefore be added to the list of other diseases with this property, including those caused by MRSA, West Nile virus, Streptococcus Pneumonia, and certain cancers, such as chronic myeloid leukemia and brain cancers. In addition, incidence of severe disease and mortality due to COVID-19 are both higher in men, consistent with the degree to which thymic involution (and the decrease in T-cell production with age) is more severe in men compared to women. For under 20s, COVID-19 incidence is remarkably low.

A Bayesian analysis of daily hospitalisations, accounting for contact-based and environmental transmission, indicates that non-adults are the only age group to deviate significantly from the exponential relationship. Our model fitting suggests under 20s have 53-77% additional immune protection beyond that predicted by strong thymus function alone. We found no evidence for differences between age groups in susceptibility to overall infection, or, relative infectiousness to others. The simple inverse relationship between risk and thymus size we report here suggests that therapies based on T-cell mechanisms may be a promising target.

Link: https://doi.org/10.1101/2020.08.25.20181487

In today's open access paper, researchers report that long-term supplementation with nicotinamide riboside in mice, starting from mid-life and continuing into old age, slows the pace of osteoporosis. The extracellular matrix of bone tissue is constantly remodeled over time, broken down by osteoclasts and built up by osteoblasts. Osteoporosis is caused by a growing imbalance between these two processes that favors destruction over creation. Bones lose mass and become brittle as a result, eventually becoming a serious health issue.

Many mechanisms are proposed to contribute to osteoporosis. Chronic inflammation, for example, alters the behavior of bone cells in ways that favor the activity of osteoclasts. Senescent cells accumulate with age and the source of a great deal of inflammatory signaling. Selectively destroying senescent cells via senolytic treatments has been shown to reverse osteoporosis to some degree. Another related mechanism involves the formation of advanced glycation endproducts (AGEs) that cross-link matrix proteins. This also is thought to be related to the chronic inflammation of aging.

Of relevance to today's research materials, mitochondrial dysfunction is also implicated in the development of osteoporosis, via its effects on cell development and activities. Mitochondria are the power plants of the cell, and when the supply of chemical energy store molecules created by mitochondria is diminished, near all cell processes suffer in some way.

In recent years, loss of NAD+ has been identified as one of the proximate causes of this issue, this being an important component in the chemical engines that operate inside mitochondria. NAD+ levels fall with age, for reasons that are far from fully explored. Various approaches to NAD+ upregulation have been assessed in mice and human trials, mostly supplementation with compounds derived from vitamin B3 such as nicotinamide riboside. The results in humans have overall been mixed at best. Nonetheless, results such as this one continue to accumulate in mice.

A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging

Here we show that NAD+ supplementation by the NAD+ precursor nicotinamide riboside (NR) can restore a youthful number of osteoprogenitor cells and attenuate skeletal aging in female mice. These, along with the findings that the levels of NAD+ decline with age in osteoblast progenitors, strongly suggest that NAD+ is a major target of aging in osteoblastic cells. A decrease in NAD+ was also seen in bone marrow stromal cells from 15-month-old when compared to 1-month-old mice. In agreement with our findings, long-term administration of NMN increased bone mineral density in male C57BL/6 mice. In contrast, administration of NMN to 12-month-old mice for only 3 months was not sufficient to alter bone mass.

We also found that the protein levels of Nampt in osteoblastic cells from old mice were lower than in cells from young mice. These along with the findings that deletion of Nampt in mesenchymal lineage cells is sufficient to decrease bone mass support the premise that the age-associated decrease in NAD+ in osteoblast progenitors attenuates bone formation. Further support is provided by evidence that NR administration increases osteoprogenitor number and mineralizing surface in aging mice. In tissues such as muscle and intestine, progenitor cells are critical targets of the anti-aging effects of NR. Nonetheless, the systemic nature of NR treatment precludes definitive conclusion about the target cells responsible for the beneficial effects on the skeleton.

We and others have shown that osteoprogenitors from old humans or mice exhibit markers of cellular senescence. Elimination of senescent cells via genetic or pharmacologic manipulations increases bone mass in aged mice, suggesting that cellular senescence contributes to skeletal aging46. Our present findings that NR administration decreases markers of senescence in osteoblast progenitors from old mice provide strong support for the contention that a decline in NAD+ is a major contributor to the age-associated bone cell senescence. This contention is further supported by evidence that a decrease in NAD+ exacerbates replicative senescence in bone marrow-derived stromal cell cultures. NR administration also attenuates cellular senescence in brain and skin of aged mice. Interestingly, in macrophages and endothelial cells Cd38 expression can be induced by factors associated with the senescence-associated secretory phenotype (SASP), suggesting that cellular senescence re-enforces the decline in NAD+.

Based on the results of the present work, we propose that intrinsic defects in osteoblast progenitors that cause a decrease in NAD+ contribute to the age-related decline in bone formation and bone mass. Repletion of NAD+ with precursors such as NR, therefore, may represent a therapeutic approach to age-associated osteoporosis as it does for other age-related pathologies.

In the past few years Jim Mellon, high net worth investor and philanthropist, has put in a great deal of time and effort to help push forward the development of a biotech industry focused on intervention in human aging. He has donated to non-profits in the aging research space, set up aging-focused conference series, founded and raised funding for a sizable biotech company in the space, invested in other biotech startups personally, and in general has been very personable and helpful to his fellow travelers and advocates. Would that there were more people with the resources and will to dive into advancing the state of the field in this way.

How does an idea that is too unconventional for mainstream channels get funded? Today, the concept of longevity research is rapidly gaining adoption, but it wasn't long ago that angel investors and the rare NIH grant were the only options for people fighting for increased longevity. Longevity enthusiasts are likely to know names like Peter Thiel, Dmitry Itskov, J. Craig Venter, Sergey Brin, Larry Ellison, and Jeff Bezos for their personal contributions, both as philanthropists and investors. Among angel investors, Jim Mellon was one of the earliest adopters of longevity research. While his fortune has come from various other sectors, he founded Mann Bioinvest, published Cracking the Code, and started praising the healthy longevity strategy back in 2012. With all the progress and setbacks of the last decade, Jim remains optimistic about the field, recently claiming that the world is on the brink of three major revolutions, with increased longevity being one of them.

In biotech, Jim Mellon is most well-known for his role in Juvenescence, which is both a book he authored on biotech investment and a longevity company he co-founded. Juvenescence has its hand in tissue regeneration and cell therapy approaches to healthy longevity via AgeX Therapeutics and LyGenesis. While still at the preclinical stage, LyGenesis has been perhaps the most successful tissue engineering and regenerative medicine company thus far. Separately from Juvenescence, Jim Mellon also played a role as chairman of Regent Pacific during its acquisition of AI firm Deep Longevity last year. He's also invested in Repair Biotechnologies and various other companies outside the scope of Juvenescence.

Beyond his investments, Jim Mellon has also made various donations to longevity nonprofits in recent years, including the UCL Institute of Healthy Ageing, Methuselah Foundation, and SENS Research Foundation, among others. In 2020, he donated £1 million to Oriel College in order to support and advance the study of Longevity Science at Oxford University, the largest donation of its kind.

For better or worse, high-net-worth individuals are imperative to the translation of treatments from the bench to bedside. While some media organizations make negative comments that billionaires are simply attempting to buy their own immortality without regard for anyone else's health, these concerns are largely overblown. Overall, few people have done as much to increase human longevity as Jim Mellon. Beyond putting up his own capital, he's also played a major role in convincing others to do the same, thereby accelerating longevity research and moving us towards a healthier future.

Link: https://www.lifespan.io/news/jim-mellons-funding-of-longevity-projects/

The study here is carried out in horses, but it is reasonable to expect to find very similar mechanisms in other mammals. The beneficial populations of the gut microbiome provide metabolites that steer cell function and exist in symbiosis with the host animal. Mitochondria, the power plants of the cell, are the evolved descendants of ancient symbiotic microbes, now an integral part of cellular processes. It is reasonable to think that the one can influence the other directly via signaling processes, as researchers discuss in these materials and elsewhere. In humans, for example, researchers have found that propionate generated by some populations of gut microbes can enhance athletic performance. There are no doubt other signals and metabolites at work as well, yet to be cataloged.

Mitochondria, which can be briefly described as the energy provider of cells, have been shown in recent studies to be interdependent with gut bacteria. In fact, many diseases associated with mitochondrial dysfunction in humans, such as Parkinson's and Crohn's have been linked to changes in the gut microbiome in many previous studies.

"Studying horses is a good way to assess the link between gut bacteria and mitochondria, because the level of exercise, and thereby mitochondrial function, performed by a horse during an endurance race is similar to that of a human marathon runner. For this study we took blood samples from 20 healthy horses of similar age and performance level, at the start and end of the International Endurance Competition of Fontainebleau, an 8-hour horse race in France. These samples provided information about the chemical signals and expression of specific genes, which is the process by which DNA is converted into instructions for making proteins or other molecules. To understand the composition of the horse's gut bacteria metabolites, we obtained fecal samples at the start of the race."

The researchers found that certain bacteria in the gut were linked to the expression of genes by the mitochondria in the cells. Furthermore, the genes that were expressed, or "turned on", were linked to activities in the cell that helped it to adapt to energetic metabolism.

"Interestingly, mitochondria have a bacterial origin - it is thought they formed a symbiotic relationship with other components to form the first cell. This may explain why mitochondria have this line of communication with gut bacteria. Improving our understanding of the intercommunication between the horse and the gut microbiome could help enhance their individual performance, as well as the method by which they are trained and dietary composition intake. Manipulating the gut microbiota with probiotic supplements as well as prebiotics, to feed the good bacteria, could be a way for increasing the health and balance of the microbiome and horses, to better sustain endurance exercise."

Link: https://www.eurekalert.org/pub_releases/2021-04/f-gb040121.php

The gut microbiome is a highly varied collection of microbial populations that acts in symbiosis with the body to process food and provide needed metabolites. With age, there is a detrimental shift in these populations. Those generating useful metabolites, such as butyrate, diminish in number. Those capable of infiltrating tissue, generating inflammatory compounds, or otherwise interacting with the immune system to provoke chronic inflammation increase in number. Researchers have demonstrated that this is a meaningful process in short-lived species by transplanting a youthful gut microbiome into older individuals. In killifish, for example, this produces extension of life. In mice, it has been shown to beneficially change measures of metabolic aging. In aged humans, better health at a given age corresponds to a younger gut microbiome configuration.

In today's open access review paper, researchers look at just one set of processes that may be influenced by the gut microbiome, those contributing to age-related anabolic resistance. Muscle growth depends on anabolism - the construction of proteins needed for cellular structures, new cells, and tissue mass - and an aged body does not produce the same level of anabolic response to stimuli such as exercise or increased protein intake. This leads to sarcopenia, the characteristic, steady loss of muscle mass over the years. Why does anabolic resistance arise with age? It is proposed that the changing populations of the gut microbiome play a role, though as is usually the case in aging, assigning a relative importance to different processes is considerably harder than identifying those processes in the first place.

Evidence for the Contribution of Gut Microbiota to Age-Related Anabolic Resistance

The aging process is associated with pervasive physiological declines that are exemplified by reductions in size and function of skeletal muscle (i.e., sarcopenia). Given the association between sarcopenia with adverse health outcomes (e.g., falls, fractures, and mobility limitations) and mortality, a more definitive understanding of the biological mechanisms underlying sarcopenia is warranted.

The regulation of skeletal muscle mass is dictated by temporal fluctuations in muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Though the effect of aging on whole body protein turnover was initially a subject of great contention, it is now generally accepted that healthy aging is not accompanied by accelerated MPB. Furthermore, comparable rates of basal MPS and turnover have been observed in healthy older and younger adults. However, in older animals and humans alike, the sensitivity of MPS to anabolic stimuli, such as protein feeding, is substantially diminished when compared with that in the young. This blunted anabolic responsiveness, termed anabolic resistance, is highly characteristic of aging skeletal muscle, and much effort is being devoted to delineating the etiology of this phenomenon. Greater insight into this area may help to optimize the rehabilitative role of protein intake for the maintenance and/or recovery of skeletal muscle tissue in older adults.

The gut microbiota refers to the collective of bacteria, archaea, viruses, and eukaryotic microbes that reside in the gastrointestinal tract. Though best known for its role in nutrient uptake, the gut microbiome is also intricately connected to a diverse array of physiological systems; influencing metabolic function, protecting against pathogens, and modulating immune response. Recent studies by several independent research groups have provided evidence for a bidirectional gut-muscle axis with profound implications for aging skeletal muscle and sarcopenia. As studies supporting a role for the gut microbiome in regulating muscle mass and function continue to accumulate, whether baseline microbial signatures may influence anabolic potential is deserving of deeper inquiry.

The purpose of this review will be to provide evidence in support of the hypothesis that age-associated changes in gut microbiota composition contribute to anabolic resistance following protein feeding in older adults that underlie sarcopenia. We will begin by outlining how changes in gut microbiota that are hallmarks of aging may impact protein digestion and amino acid absorption, reduce circulating amino acid availability, contribute to anabolic hormone deficiencies or impair responsiveness, and play a role in intramuscular signaling deficits - all of which may underlie age-related anabolic resistance.

A bidirectional gut-muscle axis with implications for aging skeletal muscle size, quality, and function has been proposed. Extending on this aging gut-muscle axis, we propose that age-related changes in gut microbiota may detract from the anabolic response of skeletal muscle to protein feeding in older adults. Intriguingly, many of these adverse microbial modifications seem to be avoided in long-lived models of highly successful aging. Through the above, we describe how commonly observed age-related changes in the gut microbiome may compromise anabolic responsiveness through their impact on protein digestion and amino acid absorption, circulating amino acid availability, anabolic hormone production and responsiveness, and anabolic intramuscular signaling.

While some of these age-associated gut microbiome alterations may simply be a product of the natural aging process, we believe that lifestyle modification (i.e., improved diet, exercise, sleep, and reducing medication use) may help to preserve gut microbial equilibrium in a manner that would be anticipated to maintain anabolic capacity in older years. To validate this hypothesis, interventional studies attempting to manipulate microbial ecology as a means to potentiate muscle protein synthetic responses to anabolic stimuli (i.e., protein feeding) in older individuals are needed.

The immune system is intimately involved in tissue function throughout the body, but particularly so in the brain. The immune system of the brain is distinct from that of the rest of the body, the two separated by the blood-brain barrier, and the immune cells of the brain participate in a range of activities necessary to the function of neurons, as well as the creation, destruction, and maintenance of synaptic connections between neurons. It isn't surprising to find links between immune aging, inflammatory signaling, and dysfunction of many systems in the brain. The focus in the commentary noted here is on age-related loss of neurogenesis, the creation of new neurons from neural stem cells, followed by their integration into existing neural circuits. Immune cells contribute to this loss of neural stem cell activity via their inflammatory signaling.

Why neurogenesis is attenuated in elderly individuals is an intriguing question that has raised renewed interest. Mechanisms associated with declined neurogenesis in the aged brain have been attributed to inflammatory cytokines. More recently, a specific role for interferon-γ (IFN-γ) produced by CD8-expressing cytotoxic T cells has been implicated. These observations suggest a scenario in which neurogenesis, at least in part, is regulated by immune cells within the aging brain. This raises several interesting questions with regards to the characteristics of specific immune cells within the brain, the signals for their expansion and maintenance, and their role in affecting neurogenesis and cognition during normal brain aging.

Further detailed insights into these processes have now been provided. In a recently published study, researchers analyzed the subtypes, frequencies, and location of immune cells in young and aged brains. Strikingly, an abundant population of natural killer (NK) cells in the dentate gyrus of brains from old humans was observed. NK cells are innate lymphocytes, with some adaptive features, that normally play a critical role in fighting virus infections and tumors. These NK cells outnumbered neutrophils, monocytes, and adaptive T lymphocytes and B lymphocytes in the brain, and were characterized by the expression of specific activation and cytotoxicity markers. These and other observations led the authors to conclude that NK cells may accumulate in specific regions of the human brain with age, in particular in the dentate gyrus. Similar observations were made in mouse studies.

It was found that the NK cell chemokine CCL3 and the growth factors GM-CSF, IL-2 and, particularly, IL-27 were produced in relatively high amounts in the interstitial fluid of the aged dentate gyrus. In studies determining whether IL-27 derived from aged neuroblasts was necessary for local expansion and accumulation of NK cells in the aged dentate gyrus, it was observed that an IL-27-neutralizing antibody blocked these effects. Together, these and other results suggested that neuroblasts sustain NK cells and augment their cytotoxicity in the aged dentate gyrus mediated, at least in part, via IL-27.

In summary, in the brain, NK cells increase with age. They predominantly reside in the dentate gyrus, a neurogenic niche where neuroblasts are also found. As the brain ages, neuroblasts undergo cellular senescence, start to express RAE-1, and produce high levels of IL-27 that induces expansion of NK cells. Notably, RAE-1 is a ligand for the NK cell activation receptor NKG2D. These age-related alterations trigger cytotoxic activity by the NK cells leading to loss of neuroblasts, concomitantly preventing regeneration of neurons resulting in cognitive decline.

Link: https://doi.org/10.1007/s12264-021-00654-3

Many approaches shown to slow aging in animal studies involve an increased efficiency of cell maintenance processes such as the ubiquitin-proteasome system and various types of autophagy. Here researchers discuss the improvement of autophagy in order to slow the age-related decline of mitochondrial function. Mitochondria are the power plants of the cell, with the vital role of producing chemical energy store molecules to power cellular operations. Autophagy involves targeting damaged cell structures and molecules for recycling, conveying them to be engulfed by a lysosome for disassembly into raw materials that can be reused. The subset of autophagic processes targeting damaged mitochondria for removal is termed mitophagy. Loss of mitochondrial function with age appears connected to a loss of efficiency in mitophagy, allowing for worn and dysfunctional mitochondria to persist in a cell, with various lines of supporting evidence arriving at this conclusion from different directions.

Aging manifests in a continuous decline of organismal homeostasis. Accumulating defects on the cellular level can result in cellular dysfunction that impairs normal physiology. This damage can be of extrinsic origin e.g., mutagenic radiation and toxins, or intracellular origin, like harmful reactive oxygen species (ROS) generated by defective mitochondrial respiration, advanced glycation end products or the accumulation of toxic protein aggregates. The consequences of such harm are particularly devastating to post-mitotic, fully differentiated cells with low cellular turnover rates, such as neuronal cells and cardiomyocytes.

To mitigate the detrimental effects of extrinsic and intrinsic harms, eukaryotic cells have developed various protective mechanisms. One such mechanism is proteostasis, a collective term for a network of protein quality control and degradation pathways that ensure the normal expression, folding, and turnover of proteins. During aging, proteostasis, like other cellular functions, suffer from a progressive decline, which renders the body more vulnerable to damage and age-related diseases.

In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.

Link: https://doi.org/10.3389/fcell.2021.656201

The ability to cryopreserve and thaw organs via vitrification, without ice formation and significant tissue damage, allowing for indefinite storage time, would go a long way towards simplifying the logistics and reducing the costs of present organ donation and future tissue engineering of organs for transplantation. Cryopreservation via vitrification also offers the possibility of indefinitely storing the terminally ill and recently deceased until such time as medical science advances to the point of restoration. This has been practiced for several decades by the small cryonics industry.

Cryonics is a long shot, but better odds by far than the grave. The challenges to progress in cryonics seem largely technical: it is presently possible to vitrify organs, but thawing them safely is another story entirely. Scaling up the reliability of vitrification processes to the whole body continues to be a work in progress, even while practiced by the cryonics community. The funding for technological progress in this field remains sparse, a situation that could be remedied by an industry of organ cryopreservation associated with donation and transplantation. Given a world in which it is routine to vitrify and thaw donated organs, it will be far easier to accept the cryopreservation of terminally ill individuals in hope of a better, more capable future, and more funds will be drawn to that goal.

Cryopreservation has multiple and important applications, particularly in medicine. The fact that it can significantly slow down all biochemical reaction kinetics renders cryopreservation highly attractive as a means to preserve organs and therefore facilitate the transplantation process. The lack of organ availability constitutes a major challenge and a significant medical burden for society. According to the World Health Organization (WHO), only 10% of the worldwide need for organ transplantation was met in 2010. The lack of transplantable organs stems partially from a shortage of suitable donated organs, but more importantly from the lack of preservation capability. Although the number of transplanted organs is much lower than what is actually needed worldwide, it was estimated that approximately two thirds of potential donor hearts are discarded.

Kidneys and hearts have been the most widely studied organs, but neither has been consistently recovered after cooling to temperatures lower than -45 °C. Nevertheless, sporadic survival of kidneys has been claimed after cooling to lower temperatures. Along those lines, researchers reported success in vitrifying a rabbit kidney at -130 °C which was rewarmed using a special conductive warming technique combined with perfusion. After warming, the kidney was transplanted into a recipient rabbit that lived for 48 days with a working kidney before being sacrificed.

Cryopreservation is an interdisciplinary endeavour between medicine, biology, bioinformatics, chemistry and physics. The main challenges still to overcome are scaling up current methods to larger volumes and complex tissues. The larger the organ, or tissue volumes to be vitrified, correspondingly more time is required to cool and warm the organ. Not only thermal conductivity is an issue here but cryoprotective agent (CPA) viscosity limits for perfusion systems play a role. The protocols for cell lines, or even small tissues, such as sperm, eggs, or corneas, cannot be replicated in larger human organs, which necessitate toxically high CPA concentration to inhibit ice formation during the longer time spent between the melting temperature and the glass transition temperature, and of course gives more time for toxic insults to accumulate.

The best techniques to get around these problems in small tissues use combinations of CPAs to reduce toxic effects of any single agent, using CPAs with weak water interactions to minimise disruption of hydration layers around biomolecules, using CPAs with mutual toxicity neutralisation effects, and reducing penetrating CPA concentrations by adding non-penetrating CPAs and ice blockers. Nonetheless, little is known about the mechanisms at work.

The challenges in cryobiology are not insurmountable. Future research will focus on ever more complex ways to prevent ice formation and mitigate cryoprotectant toxicity; novel cryoprotectants which exert disproportionately large cryoprotective effects compared to their concentration, in silico molecular modelling, and enhanced understanding of the processes that occur during cryopreservation will all be employed. One could envision a universal cryoprotectant solution, suitable for use in a range of tissue types, and physical advancements enabling high cooling and warming rates, or the manipulation of ice formation for large volume vitrification or freezing.

Whilst the concepts have been long known, the dedicated field of cryobiology dates back only around 70 years. In that time, it has advanced from freezing spermatozoa using glycerol, to vitrifying tissues, and even small organs using complex multi-component solutions. This is remarkable progress given that cryopreservation is as yet a relatively niche field of study, without garnering much attention in schools or undergraduate courses and utilising a fraction of the funding which is allocated to other causes. As such, there are still many opportunities that lie ahead, from short-term improvements in transplantation biology, to ambitions that may once have been viewed as science fiction, such as the building of organ banks or long-term suspended animation.

Link: https://doi.org/10.1186/s12915-021-00976-8

Researchers here use a novel model to demonstrate that T cells made to exhibiting the greater replication and differentiation characteristic of an aged immune system, leading to cellular senescence, cause chronic inflammation in heart tissue in young animals. The age-related decline of the adaptive immune system is thus sufficient to cause this sort of issue in and of itself, independently of other contributing causes, leading to tissue dysfunction. Clearing out harmful immune cells via senolytic drugs or other targeted approaches is one option, but a source of replacement T cells is also needed. A large part of the dysfunction of the aged adaptive immune system arises because the thymus, where T cells mature, atrophies in later life. Medical development must focus on at least two goals: restoring the thymus and selectively destroying harmful T cells.

The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage.

Herein, we sought to clarify the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions.

In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages, and dendritic cells in the heart.

Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.

Link: https://doi.org/10.3389/fimmu.2021.584538

Researchers here show that increased levels of cap-independent translation (CIT) of messenger RNA (mRNA) take place in a diverse set of interventions known to modestly slow aging in mice, suggesting it to be a common phenomenon in these shifts of metabolism towards a slower pace of aging. CIT is a process that in part drives the movement of mRNA, produced from genetic blueprints, into ribosomes for the production of proteins. Since protein levels determine cell behavior, the way in which translation of mRNA into proteins takes place is important. The work here makes a compelling case to link altered CIT levels to mTORC1 inhibition, suggesting that mTOR, already a popular area of study, may play a role in more age-slowing interventions than thought.

Several dietary and pharmacological treatments are known to extend lifespan, including rapamycin (Rapa), acarbose (ACA), and 17-α-estradiol (17aE2). The mechanisms by which these treatments lead to lifespan extension are not well understood. Rapa inhibits the activity of the mammalian target of rapamycin (mTOR), leading at optimal doses to 20%-25% lifespan extension in male and female mice. ACA is an inhibitor of the α-glucosidase hydrolase enzymes and α-amylases, enzymes that digest carbohydrates in the small intestine, leading to reduction in glucose absorption and in peak glucose levels in blood. ACA extends lifespan by around 20% in males and around 5% in female mice. 17aE2 is a non-feminizing steroid that has a reduced affinity for the classical estrogen receptors. 17aE2 has reproducible and robust effects on male median and maximum lifespan, with no lifespan effect in females.

We hypothesized that Rapa, ACA, which both increase mouse lifespan, and 17α-estradiol, which increases lifespan in males (17aE2) all share common intracellular signaling pathways with long-lived Snell dwarf, PAPPA knockout, and growth hormone receptor knockout mice. The long-lived mutant mice exhibit reduction in mTORC1 activity, declines in cap-dependent mRNA translation, and increases in cap-independent translation (CIT).

Here, we report that Rapa and ACA prevent age-related declines in CIT target proteins in both sexes, while 17aE2 has the same effect only in males, suggesting increases in CIT. mTORC1 activity showed the reciprocal pattern, with age-related increases blocked by Rapa, ACA, and 17aE2 (in males only). METTL3, required for addition of 6-methyl-adenosine to mRNA and thus a trigger for CIT, also showed an age-dependent increase blunted by Rapa, ACA, and 17aE2 (in males). Diminution of mTORC1 activity and increases in CIT-dependent proteins may represent a shared pathway for both long-lived-mutant mice and drug-induced lifespan extension in mice.

Link: https://doi.org/10.1016/j.tibs.2018.04.011

The Interventions Testing Program (ITP) at the National Institute on Aging runs very rigorous, costly life span studies in large numbers of mice, picking a few interventions to test each year. The usual outcome is that a treatment with some interesting past results is found to have absolutely no effect on life span when run through the rigor of the ITP process. We should all bear this in mind whenever modest life span extension in mice is reported by researchers elsewhere in the community. Based on past ITP data, a great many such results are the result of chance or poor experimental design.

Will the ITP ever get around to testing senolytics or other potential rejuvenation therapies? They are dosing a group with fisetin, but overall their bias is towards approved drugs and existing supplements, calorie restriction mimetics, and similar classes of intervention that affect metabolism in well-explored ways: insulin signaling; blood pressure; inflammation; and so forth. Senolytics are likely not yet a well trodden enough path for most to get past the selection process.

Today's open access paper reports the latest set of interventions to have shown minimal, gender specific, or no effects at all on mouse life span in the ITP process. Of interest to the community here, nicotinamide riboside supplementation is one of these, and does not extend mouse life span. We might compare that outcome to the 2016 paper in which mouse life span does increase modestly, the human trial in which benefits to cardiovascular function result, and all of the other data showing improved stem cell and tissue function in mice and humans.

We might view the ITP as a steamroller encouraging us to run faster, to aim higher, to stop messing around with approaches to aging that do not and cannot have large enough effects to matter at the end of the day. The only goal worth aiming for is robust, sizable rejuvenation of the old. We have excellent starting points in the form of the SENS proposals for repair of cell and tissue damage, and the existence of the senolytics industry indicates just how fast things can move once impressive data is produced in animal studies. More of that sort of thing is much needed if we are to realize the promise of modern biotechnology.

17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex

The interventions for the present study were chosen for the following reasons:

(a) 17-α-estradiol (17aE2) is a relatively "non-feminizing" estrogen which shows reduced activation of classical estrogen receptors compared with 17-β-estradiol. It was reported that in UM-HET3 mice fed 4.8 mg 17aE2/kg (4.8 ppm) diet from 10 months of age, median male lifespans increased 12%, while 17aE2 did not alter female lifespan. Other researchers showed that using a threefold higher dose (14.4 ppm) from 10 months of age, pooled median male lifespans increased 19%; the 90% lifespan increased 12%, but females still did not benefit. Thus, only males were tested in the present study. To determine whether 17aE2 treatment is effective when initiated in older mice, males were treated beginning at 16 or 20 months of age, choosing middle age, and early old age before many natural deaths.

(b) Nicotinamide riboside (NR) is a precursor of nicotinamide adenine dinucleotide (NAD) via the cell's salvage pathway. Total NAD levels decline with age, in a wide range of species. Importantly, increasing NAD levels benefit a wide variety of tissues in species including mice and human beings. it has been suggested that NAD+ boosters may "..delay aging and age-related physical decline." It was reported that NR delays senescence of neural stem cells (SCs) and melanocyte SCs and increases mouse life span, even when given in old age (5% increase at 20 months of age).

It was reported that in mice and humans NR is bioactive when given by mouth, unlike most other nicotinamide derivatives. In a 2016 study NR improved liver function and protected against diabetic neuropathy. When fed to C57BL/6 J mice from 10 weeks of age, NR protects against high-fat diet (HFD)-induced obesity and promotes oxidative metabolism by increasing the NAD+/NADH ratio in muscle, liver, and brown adipose tissue. Researchers found that increasing NAD+ stores with NR supplementation improved muscle function and alleviated heart defects in a mouse model of muscular dystrophy. It was reported that an NR metabolite, nicotinamide, did not increase lifespan when started at 12 months in C57BL/6 J mice but improved some health outcome measures. Due to its benefits in a variety of diseases, and reports of benefits in mouse lifespans, NR treatment was proposed to increase lifespan in UM-HET3 mice.

c) Candesartan cilexetil (CC) is an angiotensin-receptor blocker, which lowers blood pressure and improves cardiovascular function and insulin sensitivity in obese, hypertensive patients. Importantly, angiotensin-receptor knockout increases lifespan of mice. Because CC is effective against age-related diseases, and sensitizes the body to insulin, and because the angiotensin-receptor knockout increases lifespan of mice, treatment with CC was hypothesized to increase lifespan.

(d) To maintain good quality protein in the body, heat shock proteins (HSPs) are vital. Geranylgeranylacetone (GGA) induces heat shock protein (Hsp70) in mammalian tissues and promotes insulin sensitivity in old mice, while it increases HSP expression in atrial tissue after heart surgery. Long-lived species, compared with related short-lived species within the same order, have elevated HSP levels in conjunction with better proteostasis. To test whether treatment with an established HSP inducer can increase lifespan in a mammalian model, UM-HET3 mice were treated with GGA.

(e) MIF098 ((3-(3-hydroxybenzyl)-5-methylbenzo[d]oxazol-2(3H)-one) is a macrophage migration inhibition factor (MIF) antagonist that regulates CD44 binding. MIF is a proinflammatory cytokine, so MIF098 reduces inflammation. This may include the chronic inflammation that increases with age, as suggested by the finding that MIF-knockout mice live significantly longer than controls. Because it is orally bioavailable and shows MIF inhibitory activity in mouse models of hyperoxic lung injury, as well as in other diseases, treatment with MIF098 was proposed to increase lifespan by decreasing chronic inflammation and disease.

Our new data show that nicotinamide riboside (NR) failed to increase lifespan. Only 17aE2 increased lifespan, and benefits in males occurred even when the drug was not fed until late middle or early old age (16 and 20 months of age, respectively). The range of ages for which treatment is effective suggests that benefits from 17aE2 do not depend on effects earlier in life, such as growth alteration. Interventions that are effective when started at a late age have considerable translational potential.

Researchers here show that, in a progeroid mouse model that exhibits high levels of cellular senescence and accelerated manifestations of aging, delivering extracellular vesicles harvested from mesenchymal stem cells has much the same effect as delivering the cells as a therapy. This illustrates the point that many of these first generation approaches to stem cell therapy produce benefits via a brief period of signaling of the transplanted cells. The cells themselves die quite quickly and near entirely fail to integrate into patient tissue. Extracellular vesicles are more easily produced, stored, quality controlled, and used, overall a much better prospect from a logistical point of view. This is why there is presently such a focus on the development of therapies based on this approach.

A characteristic of aging is the loss of regenerative capacity, which leads to an impaired ability to respond to stress and therefore increased morbidity and mortality. This has led to the hypothesis that aging is partly driven by the loss of functional adult stem cells necessary for maintenance of tissue homeostasis. Indeed, mice greater than two years of age have a significant reduction in the number and proliferative capacity of various types of adult stem cells.

We previously demonstrated that muscle-derived stem/progenitor cells (MDSPC) are adversely affected upon aging. MDSPCs isolated from old and Ercc1-/∆ progeroid mice have reduced proliferative capacity and impaired differentiative potential, and this dysfunction directly contributes to age-related degeneration given that transplantation of young MDSPCs extended health span and life span in ERCC1-deficient progeroid mouse models. Transplanted MDSPCs did not differentiate or migrate from the site of injection, suggesting that the therapeutic effect of MDSPCs was mediated by secreted factors acting systemically. Concordantly, co-culture of young MDSPCs with old MDSPCs resulted in renewal of old MDSPC proliferative and differentiative potential, yet the identification of factors responsible for the rejuvenation of aged MDSPCs remained elusive.

Here, we identified bone marrow-derived mesenchymal stem cells (BM-MSCs) from young animals, and lineage-directed hESC-derived BM-MSC surrogates, as a novel source of EVs with senotherapeutic activity. We demonstrate that transplantation of BM-MSCs from young, but not old mice, prolonged life span and health span in ERCC1-deficient mice. Further, conditioned media (CM) from young BM-MSCs rescued the function of aged, senescent stem cells and senescent murine embryonic fibroblasts (MEFs) in culture.

Importantly, injection of EVs from BM-MSCs from young mice extended the life span of ERCC1-deficient mice. Similarly, treatment with EVs isolated from human embryonic stem cell-derived MSCs (hESC-MSC) was capable of significantly reducing the expression of markers of senescence in cultured senescent fibroblasts as well as naturally aged wild-type and Ercc1-/∆ mice, and improving measures of healthspan in vivo. These novel results identified EVs as key factors released by young, functional stem cells that can rescue cellular senescence and stem cell dysfunction in culture and reduce senescent cell burden in vivo. Thus, functional stem cell-derived EVs represent a novel therapeutic to reduce the senescent cell burden and extend health span.

Link: https://doi.org/10.1111/acel.13337

Cerebral small vessel disease is characterized by the accumulation of small volumes of damaged tissue in the brain, the results of the rupture or blockage of tiny blood vessels. Researchers here show that the state of the blood-brain barrier predicts the pace at which this damage grows over time. The blood-brain barrier functions to ensure that only certainly molecules and cells can move back and forth from brain and bloodstream, but like all tissues it becomes dysfunctional with age. This contributes to chronic inflammation in the brain, as unwanted substances find their way into the central nervous system. It may be case that blood-brain barrier issues and the breakage of small blood vessels that produces damaged brain tissue are distinct outcomes of the same underlying mechanisms of aging and their downstream effects. To pick an obvious example, the raised blood pressure of age-related hypertension is destructive to blood vessel walls and the delicate tissues that surround them.

"Previous research has shown that disruption of the blood-brain barrier is increased in people with cerebral small vessel disease. People with cerebral small vessel disease also may have brain lesions called white matter hyperintensities. Such lesions are visible by MRI and believed to be signs of brain damage and a marker of the severity of disease. For our study, we wanted to see if a leaky blood-brain barrier was linked to degeneration of brain tissue even before these brain lesions appear. We looked at normal brain tissue, surrounding and close to the brain lesions, because we consider this 'tissue at risk.'"

The study involved 43 people with cerebral small vessel disease with an average age of 68. Researchers used MRI at the start of the study to measure the leakiness of the blood-brain barrier for each participant. They then used another brain imaging technique to measure the integrity of the tissue's microstructure surrounding brain lesions. This imaging technique was repeated two years later to see whether the brain tissue integrity has decreased.

Researchers measured the relationship between blood-brain barrier leakage and changes in brain tissue. They found the higher the tissue volume with blood-brain barrier leakage at the start of the study, the greater the loss of brain tissue integrity was around brain lesions two years later. For every 10% increase in leakage volume at the start of the study, after two years the diffusivity of the brain tissue increased by 1.4%, representing a decrease in brain tissue integrity. They also found a similar relationship involving the leakage rate of the blood-brain barrier - a higher leakage rate at the start of the study resulted in more loss of tissue microstructure around the brain lesions.

Link: https://www.aan.com/PressRoom/Home/PressRelease/4875

The overwhelming majority of type 2 diabetes patients suffer their condition because they became significantly overweight. Being significantly overweight clearly produces the metabolic syndrome that leads to type 2 diabetes, and the more visceral fat tissue, the worse off you are. In this sense type 2 diabetes is a lifestyle condition, a choice. Attempting to explain Alzheimer's disease in the same way runs into an immediate challenge, in that there is no such very clear cause and effect. Too large a fraction of significantly overweight people do not develop Alzheimer's, and being overweight doesn't appear to correlate with the better explored aspects of cellular biochemistry known to precede Alzheimer's disease.

Nonetheless, insulin metabolism is dysfunctional in the Alzheimer's brain, and clear parallels can be drawn with the insulin resistance and related mechanisms of diabetes. This has led some researchers to think of Alzheimer's disease as a type 3 diabetes, a metabolic condition. It is a popular enough idea. While type 3 diabetes is not formally recognized as a designation, when evidence for an unrelated, new form of age-related diabetes was later discovered, it had to be put forward as a type 4 diabetes to avoid confusion.

Where does this leave us on the question of whether Alzheimer's disease is a lifestyle condition that can be avoided? It is unclear as to whether this is the case or not. The idea that Alzheimer's is driven by the consequences of persistent infection (raised amyloid levels and chronic inflammation) is presently popular, and it does provide a more satisfying answer to the question of why it is that only some people with the risk factors go on to develop the condition. It is not yet conclusively proven, however, and, in any case, it is somewhat harder to choose to avoid persistent infections than it is to choose to avoid putting on weight.

New research on Alzheimer's Disease shows 'lifestyle origin at least in some degree'

For years, research to pin down the underlying cause of Alzheimer's Disease has been focused on plaque found to be building up in the brain in AD patients. But treatments targeted at breaking down that buildup have been ineffective in restoring cognitive function, suggesting that the buildup may be a side effect of AD and not the cause itself. A new study finds novel cellular-level support for an alternate theory that is growing in strength: Alzheimer's could actually be a result of metabolic dysfunction in the brain. In other words, there is growing evidence that diet and lifestyle are at the heart of Alzheimer's Disease.

Researchers examined RNA sequences in 240 post-mortem Alzheimer's Disease-impacted brains. They were looking specifically at the gene expression of nervous system support cells during two types of metabolism: glucose metabolism, where carbohydrates are broken down to provide energy, and something called ketolytic metabolism. The researchers found widespread glucose metabolism impairment in those nervous system support cells of the brains of former Alzheimer's Disease patients, but limited ketolytic metabolism impairment. The finding is significant because the brain is like a hybrid engine, with the ability to get its fuel from glucose or ketones, but in the Alzheimer's brains studied, there appears to be a fundamental deficit in the brain's ability to use glucose.

"We've turned the hybrid engine of our brains into a mono-fuel system that just fails to thrive. And so, the brain, which is progressively becoming deficient in its ability to use glucose, is now crying out for help; it's starving in the midst of plenty. The body is swimming in a sea of glucose, but the brain just can't use it. The inability to use glucose increases the value of ketones. However, because the average person is eating insulin-spiking foods so frequently, there's never any ketones available to the brain. I look at these findings as a problem we've created and that we're making worse."

Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression

Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. RNA-seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes.

In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.

A sensible diet and adherence to a program of regular exercise have a meaningful effect on late life health, as illustrated by this epidemiological study. Therapies that target the mechanisms of aging are still in the early stages of development, and few have shown impressive results in mice, let alone humans. Exercise and the practice of calorie restriction outperform near all such treatment for which robust animal or human data has been established. This will change in years ahead, but it will never be a good idea to neglect the basics of good health.

Following a routine of regular physical activity combined with a diet including fruits, vegetables, and other healthy foods may be key to middle-aged adults achieving optimal cardiometabolic health later in life, according to new research using data from the Framingham Heart Study. Cardiometabolic health risk factors include the metabolic syndrome, a cluster of disorders such as excess fat around the waist, insulin resistance, and high blood pressure. Presence of the metabolic syndrome may increase the risk of developing heart disease, stroke, and Type 2 diabetes.

Researchers noted it has been unclear whether adherence to both the U.S. Department of Health and Human Services' 2018 Physical Activity Guidelines for Americans and their 2015-2020 Dietary Guidelines for Americans - as opposed to only one of the two - in midlife confers the most favorable cardiometabolic health outcomes later in life. The physical activity guidelines recommend that adults achieve at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week, such as walking or swimming. The dietary guidelines, which were updated in January 2021, offer suggestions for healthy eating patterns, nutritional targets, and dietary limits.

In an analysis of data from participants of the Framingham Heart Study, which began more than 70 years ago in Framingham, Massachusetts, investigators examined data from 2,379 adults ages 18 and older and their adherence to the two guidelines. They observed that meeting a combination of the two recommendations during midlife was associated with lower odds of metabolic syndrome and developing serious health conditions as participants aged in their senior years in 2016-2019 examinations. Participants who followed the physical activity recommendations alone had 51% lower odds of metabolic syndrome. Participants who adhered to the dietary guidelines alone had 33% lower odds. Participants who followed both guidelines had 65% lower odds of developing metabolic syndrome.

Link: https://newsroom.heart.org/news/exercise-healthy-diet-in-midlife-may-prevent-serious-health-conditions-in-senior-years

Researchers here note the discovery of a non-invasive biomarker that can measure the pace of destruction of senescent cells. This could be used to more rapidly quantify the effectiveness of potential senolytic treatments, those capable of destroying senescent cells, thus speeding up development of the next generation of senolytic drugs. Readily available small molecule treatments (such as the dasatinib and quercetin combination) can destroy a fraction of senescent cells throughout the body, and in doing so produce rejuvenation in animal studies. Alongside bringing those first treatments to the clinic, the next goal in line is to achieve a much greater level of clearance. A great deal of work lies ahead in that optimization process.

Researchers have discovered and are developing a novel, non-invasive biomarker test that can be used to measure and track performance of senolytics: a class of drugs that selectively eliminate senescent cells. "The list of age-related diseases definitively linked to cellular senescence keeps growing, as does the number of biotech companies racing to develop drugs to eliminate senescent cells. While the field has never been more promising, the lack of a simple biomarker to measure and track efficacy of these treatments has been a hindrance to progress. We are excited to bring this new biomarker to the field and look forward to it being used in the clinic."

This work, performed in human cell culture and mice, shows that senescent cells synthesize a large array of oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids. "Lipid components of the senescence-associated secretory phenotype (SASP) have been vastly understudied. The biosynthesis of these signaling lipids promotes segments of the SASP and reinforces the permanent growth arrest of senescent cells." Oxylipins are implicated in many inflammatory conditions including cardiovascular disease and pain response. Many commonly used drugs, such as aspirin and ibuprofen, act by preventing oxylipin synthesis.

Senescent cells change their fatty acid metabolism and they do it in such a way that free polyunsaturated fatty acids accumulate inside the arrested cells where they are used to manufacture oxylipins. Researchers identified one of these fatty acids, 15-deoxy-delta-12,14-prostaglandin J2 (dihomo-15d-PGJ2), as unique to senescent cells; it accumulates inside senescent cells and is released when the cells die. In this study, mice were given chemotherapy which induces widespread senescence, followed by a senolytic drug. The biomarker was only detected in the blood and urine of mice treated with both chemotherapy and the senolytic, but not with either on its own, confirming specificity for senolysis.

Link: https://www.buckinstitute.org/news/the-first-non-invasive-biomarker-to-track-and-verify-efficacy-of-senolytic-drugs/

Upward trends in longevity started as least as early as the 16th century in some parts of the world, and earlier elsewhere. In England, it is thought that an intertwined slow growth in life expectancy and economic productivity over hundreds of years laid the foundations for the Industrial Revolution. People who expect to live longer are better stewards of long-term capital investment, and even small gains year over year compound over time to become large. Greater wealth in turn gives rise to the byproduct of technological progress, including that relating to medicine and public health. This results in a virtuous cycle of accelerating gains in wealth, health, technological prowess, and longevity.

Today's research materials are a novel view of the earlier trends in life expectancy over the last few hundred years, based on data for European scholars. One interesting observation is that groups of higher socioeconomic status exhibited the slow historical gains in life expectancy earlier than was the case for the broader population. Control of infectious disease has been a major driver of improved life expectancy. Prior to the advent of 20th century medical technologies such as antibiotics, that control largely involved public health measures such as improved sanitation, as well as personal health measures deriving from cultural practices. We might argue that the deployment and adoption of these measures was uneven, explaining the observed data. That medical scholars exhibited a shorter life expectancy than scholars of other disciplines, at least until the development of germ theory, might also reflect the importance of infectious disease on early trends in human longevity.

Leaders and Laggards in Life Expectancy Among European Scholars From the Sixteenth to the Early Twentieth Century

In this article, we focus on the European scientific elite: scholars active at universities or academies of sciences. Observing each scholar's first appointment or nomination to a scientific institution helps to overcome common methodological issues in historical populations given that the appointment can be used to define the entry into the population at risk. More importantly, taking into account each scholar's scientific field and potential membership in an academy of sciences provides new insights into the role of medicine and social status in the process of mortality improvements. Finally, in a world where face-to-face communication was essential for both knowledge transmission and enhancement, the length of productive life among the elite was an important determinant of the extent to which members of the elite were able to influence their cultural and economic environments.

Drawing on local evidence and data on specific social groups, historians and demographers have already shown that mortality gains were made in the seventeenth and eighteenth centuries. Longevity started rising as early as 1400 and continued to increase over the fifteenth century. However, this first phase has been observed in Ireland and the United Kingdom only and these findings are subject to considerable uncertainty. Even though the total sample size is large, when stretched over several centuries, the uncertainty regarding any specific time point becomes large. This phase of longevity improvements was followed by another after 1650 that has been observed throughout Europe in other studies as well. Building a database drawn from the Index Bio-bibliographicus Notorum Hominum, which contains entries on famous people from about 3,000 dictionaries and encyclopedias, researchers found no trend in adult longevity among individuals born before the second half of the seventeenth century. Their findings also suggest that permanent improvements in longevity preceded the Industrial Revolution by at least a century. The longevity of famous people increased steadily starting with the generations born in the 1640-1649 period and grew by a total of roughly nine years in the following two centuries.

Although these studies are important, they are not without weaknesses. In the populations they studied, who belonged to the sample and when people entered the population at risk could not be precisely defined. Some of the individuals in these populations, such as famous martyrs, might have entered at death; others, such as artists, may have entered post mortem; and still others, such as members of royal families, entered at birth. In this study, we present data that overcome such weaknesses and use these data to reanalyze the timing of mortality improvements among the European elite. Furthermore, using information about relative status within the elite, we investigate whether differences in socioeconomic position were already influencing mortality when secular changes in mortality first started, or whether this pattern is more recent. Finally, we exploit information about the scientific fields in which the scholars in our database were working to examine whether there were leaders or laggards by discipline. A particular focus of our analysis is on medicine, which may have had both positive and negative effects on longevity, depending on whether the benefits of medical knowledge offset the added hazards resulting from exposure to pathogens.

We build a large, new data set with more than 30,000 scholars covering the sixteenth to the early twentieth century to analyze the timing of the mortality decline and the heterogeneity in life expectancy gains among scholars in the Holy Roman Empire. The large sample size, well-defined entry into the risk group, and heterogeneity in social status are among the key advantages of the new database. After recovering from a severe mortality crisis in the seventeenth century, life expectancy among scholars started to increase as early as in the eighteenth century, well before the Industrial Revolution. Our finding that members of scientific academies - an elite group among scholars - were the first to experience mortality improvements suggests that 300 years ago, individuals with higher social status already enjoyed lower mortality. We also show, however, that the onset of mortality improvements among scholars in medicine was delayed, possibly because these scholars were exposed to pathogens and did not have germ theory knowledge that might have protected them. The disadvantage among medical professionals decreased toward the end of the nineteenth century. Our results provide a new perspective on the historical timing of mortality improvements, and the database accompanying our study facilitates replication and extensions.

Regular exercise improves many aspects of health in later life. It reduces incidence of age-related disease and mortality risk by a significant degree. It improves near all aspects of metabolism, and reverses the downward decline of many metrics of health and aging. Hunter-gatherer populations that sustain high levels of physical activity into later life exhibit a fraction of the cardiovascular disease of populations in wealthier parts of the world. The work here illustrates another known relationship: that active older individuals have a better immune function than their less active peers, as exercise improves the measured immune cell population metrics.

Regular physical activity has a profound effect on normal functioning of the immune system. For decades it has been accepted that prolonged periods of high-intensity exercise could depress immunity. However, current evidence from epidemiological studies shows that leading a physically active lifestyle is likely to be beneficial rather than harmful to the immune function. Exercise-induced improvements in immunity can be related to reduction in inflammation, maintenance of thymic mass, changes in the composition of memory and naïve T lymphocytes or enhanced immunosurveillance. Indeed, physical activity is a powerful intervention that has a great potential to improve immune and health outcomes in the older adults, the obese, and patients with cancer and chronic viral infections. The benefits of regular physical activity undertaken by the older adults are much less documented than the effects of regular physical activity on the immune system in young individuals.

In recent years the effects of regular physical activity on T lymphocytes have attracted a considerable interest and plenty of evidence showed the lifestyle exercise may lead to rejuvenation of the immune system and may exert a positive effect on thymic output. The active older adults in our study were observed to have a statistically significantly increased percentage of blood CD4+CD45RA+ T lymphocytes in comparison to the inactive older adults. This may be associated with elevated IL-15 levels that affect the immune homeostasis which is caused by the induction of a better survival rate of naïve T lymphocytes.

Attempts to determine the relationships between cytomegalovirus (CMV)-seropositivity and changes in the count of T lymphocytes have been undertaken by scientists for many years. The results of the research carried out due to the health condition of the examined patients, genetic background and/or many others factors in highly diverse human populations are varied. Most researchers agree that CMV infection at least accelerates the age-related decrease in the number of naïve T lymphocytes and the increase in memory T lymphocytes.

In our study, we showed that, regardless of CMV-seropositivity, in the physically active older adults there was an increase in the count of CD4+CD45RA+ T lymphocytes as well as in the CD4+CD45RA+/CD4+CD45RO+ ratio compared to the inactive CMV-seropositive older adults. This emphasises the beneficial effect which the activity of older adults exerts on their immune system functioning. Latent infection in people with normal immunity frequently shows no symptoms, but it could be dangerous for immune compromised ones. This is associated with CD4/CD8 < 1 identified in immune-risk individuals, which induces a high risk of mortality due to weaker immune response. In our study, the inactive older adults CMV-seropositive individuals showed a lower CD4/CD8 ratio compared to the active older adults CMV-seropositive adults. Interestingly, older active CMV-seronegative adults obtained the CD4/CD8 ratio of 2.8 ± 1.5 which is higher than that observed in the active older CMV-seropositive adults (2.5 ± 1.0) as well as in the inactive CMV-seropositive individuals (2.1 ± 0.9).

Link: https://doi.org/10.1186/s12877-021-02128-7

There is a much greater awareness in the scientific community of the importance of cellular senescence to aging. Senescent cells are influential in the progression of many facets of aging and age-related disease, and a new industry is working to produce senolytic therapies to clear senescent cells from old tissues. Further, there is funding and interesting for investigations of the many specific ways in which senescent cells cause harm. The open access paper noted here is an example of this sort of research, which the inflammatory signaling of senescent T cells is implicated as a contributing cause of detrimental age-related changes in fat tissue metabolism.

It has become evident that adipose tissue plays an endocrine function, not merely an energy reservoir pool, and exerts a fundamental influence on metabolic regulation. Adipose tissue is classified as white adipose tissue (WAT) and brown adipose tissue (BAT). BAT has been considered a key for thermogenesis to maintaining body temperature, while WAT stores and releases lipids and is involved in promoting inflammation. BAT "whitening" refers to acquisition of white adipocyte characteristics with enlarged lipid droplets and loss of normal structure and function of brown adipocyte. Age-related alteration in adipose tissues is manifested on the distribution and composition, as well as a decline in adipose tissue quality and function.

Immune cells particularly T cells accumulate in adipose tissue with advancing age, and there exists a cross talk between T cell and preadipocyte, contributing to age-related adipose tissue remodeling. Here, we compared the difference in morphology and function of adipose tissue between young (3-month-old) and old (18-month-old) mice and showed the phenomenon of brown adipose tissue (BAT) "whitening" in old mice. Flow cytometry analysis suggested an increased proportion of T cells in BAT of old mice comparing with the young and exhibited senescent characteristics.

We take advantage of coculture system to demonstrate directly that senescent T cells inhibited brown adipocyte differentiation of preadipocytes in adipose tissue. Mechanistically, both in vitro and in vivo studies suggested that senescent T cells produced and released a higher level of IFN-γ, which plays a critical role in inhibition of preadipocyte-to-brown adipocyte differentiation. Taken together, the data indicate that senescent T cell-derived IFN-γ is a key regulator in brown adipocyte differentiation.

Link: https://doi.org/10.3389/fcell.2021.637424

An interesting result is reported in today's open access preprint paper. The authors find that the life span of mice is extended by 20% or so after treatment every few weeks with serum albumin, beginning in mid-life. The researchers base their approach on noting that aging is characterized by modification of circulating serum albumin molecules, and theorize that a significant fraction of the issues arising with age are reactions to that damaged albumin. By delivering unmodified serum albumin, the damaged fraction of albumin is reduced, and the harmful reactions diminish. This is, in effect, sabotaging one of the many feedback loops in aging wherein forms of molecular damage act as signals to provoke maladaptive responses and further molecular damage.

This is most interesting when considered in the context of the beneficial effects that are reported to result from dilution of blood in old animals. Dilution studies have been carried out as a part of the ongoing debate over whether contributions to aging result from a loss of beneficial factors in circulating blood, or from the addition of harmful factors to circulating blood. That this dilution is enough to produce some degree of reversal of aspects of aging, such as chronic inflammation, argues for the harmful factor model. It is important to note that the dilution protocol involves adding albumin, as albumin is one of the few essential items present in the bloodstream that will result in major issues should it fall to lower levels. Is the added compensatory albumin the primary cause of benefits? Further studies will be needed to clarify and replicate these results.

Young and Undamaged rMSA Improves the Longevity of Mice

Here we report that a single protein recombinant mouse serum albumin (rMSA) improved the lifespan and healthspan of C57BL/6N mice. The median lifespan extensions were 17.6% for female and 20.3% for male, respectively. The grip strength of rMSA-treated female and male mice increased by 29.6% and 17.4%, respectively. Meanwhile, the percentage of successful escape increased 23.0% in rMSA-treated male mice using the Barnes Maze test. The rMSA used in this study is young and almost undamaged. We define the concept "young and undamaged" to any protein without any unnecessary modifications by four parameters: intact free thiol (if any), no advanced glycation end-product, no carbonylation, and no homocysteinylation. Here "young and undamaged" rMSA is much younger and less damaged than the endogenous serum albumin from young mice at 1.5 months of age. We predict that young and undamaged proteins altogether can further improve the longevity.

Human serum albumin (HSA) is the most abundant protein in blood plasma with a serum half-life of about 21 days. Damages or unnecessary modifications of HSA are related to many pathological conditions and increase with age. Firstly, the single free thiol in Cys-34 residue of HSA has been proposed to account for approximately 80% of the total free thiols in plasma, whose oxidation is intimately linked with aging and age-related diseases. Secondly, in oxidative environments, carbonyls are also formed especially on the side chains of residues in proteins. Elevated carbonyl levels in HSA have been found to be related to aging and varieties of diseases. Thirdly, the AGE accumulation of HSA is another important factor found to be involved in aging. It is widely reported that AGE formation impairs normal functions of albumin and can induce inflammatory responses, which is connected with aging and the progression of serious diseases. Fourthly, it has been widely reported that homocysteine (Hcy) increases with age and is associated with age-related degenerative disorders. HSA is a major target for homocysteinylation, thus it can efficiently protect other proteins from the toxicity of Hcy.

Therefore, treatment of freshly prepared recombinant serum albumin with no damages or unnecessary modifications is most likely to extend lifespan and healthspan. Here we report that young and undamaged recombinant mouse serum albumin (rMSA)-treated groups in natural aging mouse model obtained significantly extended lifespan with increased skeletal muscle strength and cognitive ability compared with saline-treated groups.

Researchers here applied three months of a methionine restricted diet to old mice, and found that it greatly reduced age-related cognitive decline, as measured in maze tests. The methionine restricted animals perform more like young animals than like their unrestricted peers. Methionine is an essential amino acid essential to all protein synthesis. Methionine sensing is one of the more important triggers by which the beneficial response to calorie restriction is activated. Near every aspect of metabolism shifts into a more healthy, life-span-prolonging mode of operation. A methionine restricted diet thus mimics a sizable fraction of calorie restriction without eating less. The methionine restricted mice actually ate more food than their unrestricted counterparts, while having a lower body weight.

Methionine restriction (MR) extends lifespan and delays the onset of aging-associated pathologies. However, the effect of MR on age-related cognitive decline remains unclear. Here, we find that a 3-month MR ameliorates working memory, short-term memory, and spatial memory in 15-month-old and 18-month-old mice by preserving synaptic ultrastructure, increasing mitochondrial biogenesis, and reducing the brain malondialdehyde (MDA) level in aged mice hippocampi.

Transcriptome data suggest that the receptor of fibroblast growth factor 21 (FGF21)-related gene expressions were altered in the hippocampi of MR-treated aged mice. MR increased FGF21 expression in serum, liver, and brain. Integrative modelling reveals strong correlations among behavioral performance, MR altered nervous structure-related genes, and circulating FGF21 levels.

Recombinant FGF21 treatment in cell culture balanced the cellular redox status, prevented mitochondrial structure damages, and upregulated antioxidant enzymes HO-1 and NQO1 expression by transcriptional activation of Nrf2. Moreover, knockdown of Fgf21 by injection of adeno-associated virus abolished the neuroprotective effects of MR in aged mice.

In conclusion, the MR exhibited the protective effects against age-related behavioral disorders, which could be partly explained by activating circulating FGF21 and promoting mitochondrial biogenesis, and consequently suppressing the neuroinflammation and oxidative damages. These results demonstrate that FGF21 can be used as a potential nutritional factor in dietary restriction-based strategies for improving cognition associated with neurodegeneration disorders.

Link: https://doi.org/10.1016/j.redox.2021.101940

Humans evolved in an environment of physical exertion, and our biochemistry requires physical exertion in order to trigger mechanisms of cell maintenance and metabolic regulation. Populations that exercise vigorously into late old age, such as the Tsimane in Bolivia, exhibit very much lower levels of cardiovascular disease. Further, living a sedentary lifestyle shortens life expectancy and increases disease risk when compared to people who exercise even the moderate amount that is the present recommended level. The dose-response curve data for physical activity suggests that the recommended level should be a good deal higher.

Physical inactivity is a risk factor for premature mortality and several non-communicable diseases. The purpose of this study was to estimate the global burden associated with physical inactivity, and to examine differences by country income and region. Population-level, prevalence-based population attributable risks (PAR) were calculated for 168 countries to estimate how much disease could be averted if physical inactivity were eliminated. We calculated PARs (percentage of cases attributable to inactivity) for all-cause mortality, cardiovascular disease mortality and non-communicable diseases including coronary heart disease, stroke, hypertension, type 2 diabetes, dementia, depression, and cancers.

Globally, 7.2% and 7.6% of all-cause and cardiovascular disease deaths, respectively, are attributable to physical inactivity. The proportions of non-communicable diseases attributable to physical inactivity range from 1.6% for hypertension to 8.1% for dementia. There was an increasing gradient across income groups; PARs were more than double in high-income compared with low-income countries. However, 69% of total deaths and 74% of cardiovascular disease deaths associated with physical inactivity are occurring in middle-income countries, given their population size. Regional differences were also observed, with the PARs occurring in Latin America/Caribbean and high-income Western and Asia-Pacific countries, and the lowest burden occurring in Oceania and East/Southeast Asia.

Link: https://doi.org/10.1136/bjsports-2020-103640

Particulate air pollution is generally agreed upon to be harmful to long-term health, particularly from sources prevalent in poorer regions of the world such as the smoke from wood fires used for cooking. Exposure to these airborne particles raises the burden of chronic inflammation, thus accelerating the onset and progression of all of the common age-related diseases, including cardiovascular disease and dementia, and increasing age-related mortality. The mechanism is fairly cut and dried, but the size of the effect on mortality is up for debate, as is often the case. Just how many deaths does it cause?

In today's research materials, researchers report on the outcome of using updated models of mortality risk due to particular exposure. They argue that the data of recent years shows that low doses of particulates are worse than thought, while the increasingly negative effects at high doses do not plateau as early as thought. Applying this to the model gives a much greater impact of particulate air pollution on human mortality than previously though. This is nonetheless a model, in which the many different connecting parts can be adjusted one way or another based on underlying arguments for the right or wrong way to do it. This paper is one position in an ongoing debate of many positions on the topic. It is not a great plan to sit in front of a wood fire every day, but it remains hard to pin down just how bad this is.

Pollution from fossil fuel combustion deadlier than previously thought

A new study found that fine particulate pollution generated by the burning of fossil fuels was responsible for one in five early deaths worldwide in 2018-far more than previously thought. The people most at risk are those "who can least afford it." The study found that, worldwide, 8 million premature deaths were linked to pollution from fossil fuel combustion, with 350,000 in the U.S. alone. Fine particulate pollution has been linked with health problems including lung cancer, heart attacks, asthma, and dementia, as well as higher death rates from COVID-19.

Global mortality from outdoor fine particle pollution generated by fossil fuel combustion: Results from GEOS-Chem

The burning of fossil fuels - especially coal, petrol, and diesel - is a major source of airborne fine particulate matter (PM2.5), and a key contributor to the global burden of mortality and disease. Previous risk assessments have examined the health response to total PM2.5, not just PM2.5 from fossil fuel combustion, and have used a concentration-response function with limited support from the literature and data at both high and low concentrations.

This assessment examines mortality associated with PM2.5 from only fossil fuel combustion, making use of a recent meta-analysis of newer studies with a wider range of exposure. We also estimated mortality due to lower respiratory infections (LRI) among children under the age of five in the Americas and Europe, regions for which we have reliable data on the relative risk of this health outcome from PM2.5 exposure.

We used the chemical transport model GEOS-Chem to estimate global exposure levels to fossil-fuel related PM2.5 in 2012. Relative risks of mortality were modeled using functions that link long-term exposure to PM2.5 and mortality, incorporating nonlinearity in the concentration response. We estimate a global total of 10.2 million premature deaths annually attributable to the fossil-fuel component of PM2.5. The greatest mortality impact is estimated over regions with substantial fossil fuel related PM2.5, notably China (3.9 million), India (2.5 million) and parts of eastern US, Europe and Southeast Asia.The estimate for China predates substantial decline in fossil fuel emissions and decreases to 2.4 million premature deaths due to 43.7% reduction in fossil fuel PM2.5 from 2012 to 2018 bringing the global total to 8.7 million premature deaths.

This study demonstrates that the fossil fuel component of PM2.5 contributes a large mortality burden. The steeper concentration-response function slope at lower concentrations leads to larger estimates than previously found in Europe and North America, and the slower drop-off in slope at higher concentrations results in larger estimates in Asia.

Researchers here present an interesting view of how chronic inflammation affects cartilage tissue to cause the progression of osteoarthritis. A feedback loop is established between mechanisms of inflammation and mechanisms of pressure sensing, leading to the outcome of cartilage degeneration. Novel points of intervention will no doubt arise as the result of this work, with researchers seeking to break the feedback loop. The best approach still appears to be prevention of the chronic inflammation of aging, given the degree to which rising inflammation contributes to myriad age-related conditions.

An unfortunate biological "feed-forward" loop drives cartilage cells in an arthritic joint to actually contribute to progression of the disease. Cartilage is the highly lubricated, low-friction, elastic tissue that lines joint surfaces, cushioning movements and absorbing millions of cycles of mechanical compression. As cartilage breaks down in painful osteoarthritis, the ends of bones can come together bone-on-bone, increasing pain even more.

The cells that build and maintain cartilage are called chondrocytes, and on their surface can be found ion channels that are sensitive to force, called Piezo1 and Piezo2. In response to mechanical loads on the joint, Piezo channels send signals into the cell that can change gene activity in that cell. Normally, chondrocytes produce extracellular matrix, the structural proteins and other biomolecules that give cartilage its mechanical stiffness, elasticity and low friction. But in osteoarthritis, degeneration and malfunction of these cells - which are incapable of repair by cell division - contribute to the progressive breakdown of cartilage.

One of the other hallmarks of osteoarthritis is chronic, low-grade inflammation, driven by a signaling molecule called interleukin-1 alpha. Using cartilage cells from pigs and from human joints removed for replacement surgeries, the researchers wanted to see how inflammation affects chondrocytes. They found that interleukin signaling tells the cell to produce more Piezo channels, making the cell even more sensitive to pressure and resulting in what the researchers call a harmful 'feed-forward' loop that leads to more breakdown of the cartilage. "Interleukin reprograms the chondrocytes so that they're more sensitive to mechanical trauma. The feed-forward cycle slowly grinds them down and the cell cannot be replaced. It's cartilage reprogramming itself to do more damage."

Link: https://today.duke.edu/2021/03/inflammation-and-pressure-sensing-leads-%E2%80%98feed-forward%E2%80%99-loop-osteoarthritis

Heart failure causes harm to the brain by reducing the supply of blood, and thus the supply vital nutrients and oxygen, to brain cells. The precise details of how this leads to cognitive decline are yet to be fully mapped. Researchers here assess changes in gene expression the brains of mice suffering from heart failure, as a starting point for further investigation of specific mechanisms. The best path forward for this class of contribution to neurodegenerative conditions is to prevent or reverse vascular aging, which has numerous components. There is the narrowing of blood vessels via atherosclerosis; the failure of smooth muscle tissue to appropriately contract and dilate blood vessels, due to cellular senescence, chronic inflammation, and other mechanisms of aging; stiffening of blood vessels via cross-linking in the extracellular matrix; and so forth.

In heart failure, the heart muscle is too weak to pump enough blood through the body and is therefore abnormally enlarged. Physical fitness and quality of life suffer as a result. Moreover, affected individuals have an increased risk of developing dementia. "People with cardiological problems and heart failure in particular may experience noticeable cognitive deficits and increased risk of developing Alzheimer's disease. Possible reasons include impaired blood supply to the brain and dysfunction of the hippocampus, which is the memory's control center. Yet, there is a lack of therapies to effectively treat cognitive deficits in people with heart problems. This is because it is completely unclear which deficiencies are triggered in neurons. There was no data on this so far."

Researchers observed in mice that impaired gene activity developed in the hippocampus as a result of heart problems. "In memory tests, mice with heart failure performed significantly worse than their healthy mates. We then examined the neurons of the hippocampus. In the mice with heart failure, we found increased cellular stress pathways and altered gene activity in neurons."

The genome of a mouse - and also of humans - comprises around 20,000 genes. In any given cell, however, only a part of them is active, switched on, so to speak. This is not a mere on or off state: the activity can be strong or less strong. This depends, among other things, on how tightly the DNA of the genome is wound and how accessible the genes on it are. In both mice and humans, the DNA is more than a meter long. But in a cell, the molecule is so tightly packed that it fits into the nucleus. "Genes can only be active if they are accessible to the cell's machinery. To this end, the DNA needs to be wound a little more loosely at the relevant sites. This is similar to a ball of yarn with loops sticking out of it." In the current study, the DNA was found to be more tightly wound in neurons of mice with heart problems than in healthy mates. Various genes important for hippocampal function were therefore less active than in healthy mice.

Link: https://www.dzne.de/en/news/press-releases/press/a-weak-heart-is-bad-for-the-brain/

Hematopoietic stem cells (HSCs), resident in the bone marrow, are at the base of a complicated tree of descendant progenitor cells that collectively produce immune cells and red blood cells. With age, the HSC population becomes damaged and dysfunctional. The number of competent stem cells diminishes, while mutational damage followed by clonal expansion causes issues such as myeloid skew in the hematopoietic populations, in which too many myeloid cells are produced at the expense of needed lymphoid cells. This all contributes to an age-related decline in immune system function. Given the importance of the immune system to health and aging, there is considerable interest in finding ways to restore a more youthful, functional state of hematopoiesis in older people.

Today's research materials discuss chronic infection as one of the contributing causes of HSC dysfunction. In the study of aging, the more interesting chronic infections are viral, meaning persistent herpesviruses such as cytomegalovirus that the immune system cannot fully clear. The presence of infection puts a stress on the immune system, as cells replicate more rapidly, and a greater number of replacement somatic cells are required to ensure continued function. Over longer periods of time, this can lead to exhaustion of these cell populations, both the somatic cells that only replicate a limited number of times, and the stem cells that use a fine balance of mechanisms to ensure their self-renewal and continued ability to create new somatic cells.

Study reveals how long-term infection and inflammation impairs immune response as we age

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

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

Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling

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

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

Tau is involved in Alzheimer's disease and other tauopathies; it is one of the few proteins in the body capable of becoming naturally altered in ways that encourage aggregation of the protein into solid deposits that are toxic to cells. Tau is highly expressed in nerve cells, and helps in the function of the microtubule network of the cell. It also has roles in other processes peculiar to nerve cells, such as synaptic transmission. Mice lacking tau exhibit issues with regulation of insulin metabolism and behavior. That isn't preventing the exploration of lowered tau levels as a basis for therapies to treat Alzheimer's disease. In the course of that work, researchers have discovered that tau influences mitochondrial function, another hot topic in the science of aging and age-related disease.

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

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

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

Link: https://doi.org/10.3389/fnins.2020.586710

Transient ischemia is the loss of blood supply to tissue followed by its restoration, leading to cell death, tissue damage, and harmful cell signaling. While the paper here is focused on connecting the significant ischemia of stroke with the later development of Alzheimer's disease, it is also the case that aging brains undergo many unnoticed, tiny ischemic events over the years. These minuscule strokes have the same root cause as large, evident strokes, meaning the rupture or blockage of a blood vessel in the brain, but much smaller vessels and surrounding volumes of tissue are involved. That damage likely adds up over time, however, contributing to the onset and progression of neurodegenerative conditions such as Alzheimer's disease.

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

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

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

Link: https://doi.org/10.3389/fnagi.2021.636653

Naked mole-rats exhibit an unusually longevity, with a life span something like nine times as long as that of equivalently sized mammals. They are also highly resistant to cancer. This makes them an attractive subject for research into ways to treat aging and age-related disease. No one mechanism will be the exclusive source of these traits in the naked mole-rat, but it is interesting to look at the way in which cellular senescence is different in this species.

Senescent cell accumulation takes place in tissues throughout the body with advancing age, and in other mammals those senescent cells cause harm via their senescence-associated secretory phenotype (SASP), signals that provoke chronic inflammation and tissue dysfunction. Senescent cells in naked mole-rats - and in the related blind mole-rat species - on the other hand exhibit a minimal SASP.

That is not the only difference in the mechanisms of cellular senescence, as noted here. Naked-mole rat cells employ cholesterol metabolism in ways yet to be fully explored in order to make cells resistant to cellular senescence, thus reducing the number of cells that enter a senescent state. Absent this mechanism, the researchers argue that naked-mole rat cells are, if anything, even more prone to becoming senescent than those of other mammals. This is all quite interesting. In the broader context, applying treatments that reduce the pace at which cells become senescent has been shown to produce benefits to health and life span. That is achieved more slowly than clearing out senescent cells via short-term senolyic therapies, but the effect sizes may turn out to be similar at the end of the day.

β-catenin-promoted cholesterol metabolism protects against cellular senescence in naked mole-rat cells

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

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

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

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

Bat species include many that are long-lived for their size. Flying species in general are long lived; one can find many similarities in metabolism between bats and birds. It may be the case that the much higher metabolic rate of flying species requires improved mechanisms of cell resilience and cell maintenance that have the side-effect of better resisting the damage of aging. On the cell resilience side, the membrane pacemaker hypothesis considers that longer-lived species have cell membranes more resistant to oxidation by the byproducts of metabolic activity. On the cell maintenance side, we have studies such as this one, in which researchers show that bats appear to upregulate the cellular recycling mechanism of autophagy with age, and thereby presumably better clear out damaged structures and proteins.

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

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

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

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

Link: https://doi.org/10.18632/aging.202852

Cholesterol metabolism is interesting in that humans (a) do not break down cholesterol to any great degree, and (b) cholesterol is only created in a limited number of locations in the body. Thus intricate mechanisms shuffle cholesterol from place to place via the circulatory system. LDL particles carry cholesterol from the liver to the body, APOE aids in cellular update of cholesterol, ABCA1 enables cells to hand off cholesterol to HDL particles, and those HDL particles carry cholesterol to the liver. That high level sketch expands out into a much more complex picture if one looks more closely, but it gives a sense of the way in which cholesterol transport functions. These systems tend to break down in the environments of too much cholesterol, too much oxidation of cholesterol, and so forth. That gives rise to localized excesses of cholesterol and a range of conditions that include, most prominently, atherosclerosis.

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

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

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

Link: https://healthsciences.arizona.edu/newsroom/news-releases/2021/cholesterol-may-be-key-new-therapies-alzheimers-disease-diabetes