Fight Aging!

One has to be cautious about studies in which metabolism is broken in some way, and symptoms of aging start to appear earlier as a result. Whether or not this has any relevance to normal aging is dependent on the fine details of the biochemistry involved, and can often be argued either way even by those with the most knowledge in the field. Aging is an accumulation of damage and dysfunction in cells and tissues. Many genetic alterations and toxins that disrupt cell metabolism will lead to damage and dysfunction, and thus conditions that appear similar to those of aging. But unless it is the same forms and distribution of damage, and it never is, there may well be little to learn that will help in treating aging.

In today's research, the scientists involved find that deletion of TFAM from T cells in mice breaks mitochondrial function in a way that leads T cells to become highly inflammatory, pumping out signals that are known to increase the pace at which cells enter a senescent state. The mice exhibited raised levels of cellular senescence throughout the body, a characteristic attribute of older animals. Senescent cells contribute to aging via their own signaling that rouses the immune system to chronic inflammation and disrupts tissue function. The researchers tested a few interventions that partially reversed the harms done by this genetic modification, both of which are under investigation as therapies for aging, but the data from this study cannot indicate whether or not they would be useful in normally aged mice or humans. It is an example of producing a greatly exaggerated form of a dysfunction that does exist in normal aging, but to a lesser degree.

That aside, I think that this work does succeed in emphasizing the importance of mitochondrial function, chronic inflammation, and cellular senescence in aging. Scientific programs seeking to address the issue of mitochondrial decline in aging could certainly benefit with greater funding and support. Approaches to suppress chronic inflammation are popular and very well funded, but still somewhat stuck in the paradigm of blocking inflammatory signals, a strategy that has significant side-effects, rather than focusing on the root causes of overactivation of the immune system. At least we can say that work on clearing senescent cells from old tissues is finally forging ahead, better late than never.

Defective immune cells could make us old

Our T cells let us down as we age, becoming weaker pathogen fighters. This decline helps explain why elderly people are more susceptible to infections and less responsive to vaccines. One reason T cells falter as we get older is that mitochondria, the structures that serve as power plants inside cells, begin to malfunction. But T cells might not just reflect aging. They could also promote it. Older people have chronic inflammation throughout the body, known as inflammaging, and researchers have proposed it spurs aging. T cells may stoke this process because they release inflammation-stimulating molecules.

To test that hypothesis, researchers genetically modified mice to lack the TFAM protein in the mitochondria of their T cells. This alteration forces the cells to switch to a less efficient metabolic mechanism for obtaining energy. By the time the rodents were 7 months old, typically the prime of life for a mouse, they already appeared to be in their dotage. Compared with typical mice, the modified rodents were slow and sluggish. They had shrunken, weak muscles, and were less resistant to infections. Like many elderly people, they suffered from weakened hearts and shed much of their body fat. T cells from the altered mice poured out molecules that trigger inflammation, the team found, suggesting the cells could be partially responsible for the animals' physical deterioration.

The scientists also tested whether they could slow the aging clock. First they dosed the mice with a drug that blocks tumour necrosis factor alpha (TNF-alpha), one of the inflammation-inducing molecules that T cells unleash; the treatment increased the animals' grip strength, improved their performance in a maze, and boosted the heart's pumping power. The researchers also gave the animals a compound that raises levels of nicotinamide adenine dinucleotide (NAD), a molecule that's vital for metabolic reactions that enable cells to extract energy from food. NAD's cellular concentrations typically decline with age, and the researchers found that ramping it up in the mice made them more active and strengthened their hearts.

T cells with dysfunctional mitochondria induce multimorbidity and premature senescence

The impact of immunometabolism on age-associated diseases remains uncertain. Here, we show that T cells with dysfunctional mitochondria due to mitochondrial transcription factor A (TFAM) deficiency act as accelerators of senescence. In mice, these cells instigate multiple aging-related features, including metabolic, cognitive, physical, and cardiovascular alterations, which together result in premature death. T cell metabolic failure induces the accumulation of circulating cytokines, which resembles chronic inflammation characteristic of aging ("inflammaging"). This cytokine storm itself acts as a systemic inducer of senescence. Blocking TNF-α signaling or preventing senescence with NAD+ precursors partially rescues premature aging in mice with Tfam-deficient T cells. Thus, T cells can regulate organismal fitness and lifespan, highlighting the importance of tight immunometabolic control in both aging and the onset of age-associated diseases.

A fair amount of effort is presently put towards the exploration of supplements derived from vitamin B3 compounds (nicotinamide, niacin, nicotinamide riboside) that act as precursors to enable the manufacture of nicotinamide adenine dinucleotide (NAD). NAD is an important component in mitochondrial activity, and levels decline with age. Some portion of the loss of mitochondrial function, implicated in the progression of many age-related conditions, is due to NAD insufficiency. There is a rich history of the use of high doses of vitamin B3 as an intervention, most of it predating modern understanding of the role of NAD in mitochondrial biochemistry, but less work carried out with the deliberate intent of raising NAD levels.

Nicotinamide mononucleotide, discussed here, and nicotinamide riboside are the compounds of choice for modern studies aimed at raising NAD levels and assessing the resulting effects on health and tissue function, though groups like Nuchido are trying to broaden that portfolio. While this is becoming an energetic part of the field, attracting more interest over time, the data is beginning to suggest that the established means of NAD precursor supplementation are inferior to regular moderate exercise, and particularly strength training, when it comes to raising NAD levels. It remains to be seen how this settles out in the years ahead, given more scientific work on the topic.

Nicotinamide adenine dinucleotide (NAD) is a vital metabolic redox co-enzyme found in eukaryotic cells and is necessary for over 500 enzymatic reactions. It plays a crucial role in various biological processes, including metabolism, aging, cell death, DNA repair, and gene expression. The deficiency of NAD+ is closely associated with diverse pathophysiologies, including type 2 diabetes (T2D), obesity, heart failure, Alzheimer's disease (AD), and cerebral ischemia. The NAD+ levels decline in multiple organs with age, and this contributes to the development of various age-related diseases. Therefore, NAD+ supplementation could be an effective therapy for the treatment of the conditions mentioned above.

Nicotinamide mononucleotide (NMN) is one of the intermediates in NAD+ biosynthesis. In mammalian cells, NAD+ is synthetized, predominantly through NMN, to replenish the consumption by NADase participating in physiologic processes including DNA repair, metabolism, and cell death. Recent preclinical studies have demonstrated that the administration of NMN could compensate for the deficiency of NAD+, and NMN supplementation was able to effect diverse pharmacological activities in various diseases.

Given that NMN has shown high efficacy and benefits in various mouse models of human disease, several clinical trials of NMN have been conducted to investigate its clinical applicability. This has led to some capsule formulations of NMN being approved and put on the market as health supplements. The first phase I human clinical study for NMN is to examine the safety and bioavailability of NMN in human bodies. Recently, it was reported that a single oral administration of NMN up to 500 mg was safe and effectively metabolized in healthy subjects without causing severe adverse events. The major final metabolites of NMN were significantly increased in a dose-dependent manner by NMN administration.

A phase II study is also underway to assess the safety of long-term NMN in healthy subjects, the kinetics of NMN and metabolites of NAM, and the effect of daily administration of NMN on glucose metabolism. Other clinical trials of NMN are ongoing to examine the effect of NMN on insulin sensitivity, endothelial function, blood lipids, body fat and liver fat, and fat tissue and muscle tissue markers of cardiovascular and metabolic health. Additionally, a study has been initiated to evaluate the effect of long-term oral administration of NMN on various hormones in healthy volunteers. Recently, a new clinical study was initiated to evaluate the effect of NMN oral administration on the body composition in elderly persons.

In summary, despite the tremendous research efforts aimed at exploiting the therapeutic potential of NMN to treat metabolic and aging-related diseases, the clinical and toxicological evidence to support its utility is currently insufficient. Thus, further research is needed to increase the prospects of developing drugs based on NMN.

Link: https://doi.org/10.3389/fcell.2020.00246

A few varieties of dwarf mice exhibit considerable longevity. They are produced via forms of mutation that disable portions of growth hormone metabolism, such as via growth hormone receptor knockout. Most research has thus focused on insulin signaling, IGF-1, and other pathways closely tied to growth hormone. Here, scientists instead focus on the behavior of fat tissue in these long-lived mouse lineages, suggesting that the significant differences they observe in the metabolism of visceral fat may contribute to the impact on aging.

It is well known that visceral fat is metabolically active, and excess amounts create chronic inflammation through a number of mechanisms, including accelerated generation of senescent cells. That doesn't appear to happen to anywhere near the same degree in dwarf mice, and the researchers offer their thoughts as to why this might be the case. In this context, it would be interesting to compare the biochemistry of the small human population exhibiting Laron syndrome, which similarly results from a loss of function mutation affecting growth hormone metabolism. They do not appear to live any longer than the rest of us, but there are suggestions in the data that they may be modestly more resistant to some age-related conditions.

Dwarf mice were found to have functionally altered adipose tissues. Generally, three types of adipose tissue are found in mammals: white, brown, and beige. White adipose tissue (WAT) is considered the body's energy storage for times of energy scarcity while brown adipose tissue (BAT) is a unique, major energy consuming, heat producing organ. This highly thermogenic BAT, found commonly in small sized mammals and juveniles of larger-bodied mammals including humans, is very important for physiology in general and metabolic homeostasis in particular. It not only maintains endothermy but also is crucial for many physiological processes relating to decreased metabolic rate. Lastly, beige adipose is originally derived from WAT precursors but has properties more similar to BAT.

For decades, both WAT and BAT were largely excluded from evolutionary and developmental research in cell and tissue biology. Due to the common notion that adipose tissue was mainly assigned a passive role for lipid storage, insulation, and mechanical buffering it was considered a large source of unwanted biological variance due to individual feeding status and other environmental factors driving the extent and composition of WAT and BAT. More recently, WAT has been recognized as a major endocrine organ, and as such, the interest in adipose tissues has increased dramatically.

Interestingly, there seem to be peculiarities in WAT localization in homozygous long-lived Ames dwarf (AD) mice compared to normal sized, heterozygous controls. The potential differences in WAT depots compared to other laboratory mice became most visible when AD were exposed to a high fat diet containing 60% fat. Diet-induced obesity in AD seemingly did not lead to expected metabolic derangements which clearly developed in littermate controls, despite significant increases in the amount of their subcutaneous and visceral depots. Instead, "obese" AD mice remained insulin sensitive and showed normal levels of adiponectin. The adipokine adiponectin, acts as an important anti-inflammatory factor and usually correlates positively with the retention of insulin sensitivity.

We thus hypothesize here that growth hormone deficient, genetically dwarf mice, such as Ames dwarf and Snell dwarf, have a metabolic advantage when kept on high-fat diets through the storing of triglycerides preferentially in subcutaneous depots as opposed to evoking depots around the visceral organs like many common laboratory mouse models. This is important as visceral WAT is primarily associated with metabolic complications such as insulin resistance, increased inflammation, and even cancer, which have detrimental effects on tissue health and metabolism. To date, no adverse metabolic effects are described from expansion of subcutaneous WAT. Rather subcutaneous WAT has been assigned metabolic beneficial roles through its browning ability.

Link: https://doi.org/10.3390/metabo10050176

The Forever Healthy Foundation publishes a series of conservative risk-benefit analyses of presently available interventions that might prove beneficial in addressing aspects of aging. These range widely in proven effectiveness, quality of animal evidence, and theoretical utility. Some do not in any way attack the known root causes of aging. Some are still pending any sort of rigorous human trial data. Some have plenty of human data that strongly indicates small, unreliable effects at best. It is nonetheless a useful exercise to make clear which are which. In a world in which the "anti-aging" industry propagates all sorts of nonsense to sell their snake-oil products, there is a comparative lack of good, unbiased analysis of approaches that might actually work to some degree, coupled with a responsible attitude towards uncertainty and risk.

The latest publication in the Forever Healthy series covers what is probably the best of the few presently available rejuvenation therapies, the use of dasatinib and quercetin in combination as a senolytic treatment. Senolytics selectively destroy senescent cells. These cells accumulate with age, and their presence actively maintains an inflammatory, dysfunctional state of metabolism, contributing meaningfully to the progression of degenerative aging and age-related disease. In animal models, senolytic therapies produce impressive results in turning back the manifestations of a wide range of age-related diseases. It is not hyperbole to say that this data is far, far better, more reliable, and more robust than the equivalent data for any other intervention targeting aging in old animals. Several small human trials have either been conducted and are underway for dasatinib and quercetin, and the published results to date are promising but not yet conclusive.

Risk-Benefit Analysis of Dasatinib + Quercetin as a Senolytic Therapy

When a cell reaches the end of its life or becomes damaged beyond repair it normally either kills itself or signals the immune system to remove it. Unfortunately, every so often this mechanism fails. The cell stays around indefinitely and starts poisoning its environment. Over time, more and more of these harmful, death resistant, senescent cells accumulate. Senescent cells are thought to be one of the main drivers of aging and age-related diseases.

Senolytics are drugs that selectively remove senescent cells by disabling the mechanisms that allow them to survive. Dasatinib (D), a well-established medication used in the treatment of cancer and quercetin (Q), a flavonoid common in plants were among the first senolytics to be discovered. As they have been shown to affect different types of senescent cells, they are often employed in combination.

Studies in rodents have shown that clearing senescent cells can prevent, delay, or alleviate multiple age-related diseases and extend the healthy lifespan by up to 35%. Based on the promising results in animal testing, it is supposed that intermittent dosing of D+Q also leads to the elimination of senescent cells in humans with the accompanying health and rejuvenation benefits. As the first clinical trials in humans have been completed and interest in the practical application of D+Q is increasing, Forever Healthy seeks to assess the risks, benefits, and therapeutic protocols of using D+Q as a senolytic therapy.

Currently, there are only results from 3 trials in humans in which D+Q was evaluated as a senolytic therapy. The majority of human studies used D or Q in cancer therapy and provided information on side effects and safety. The benefits shown in animals were significant and were observed in many organ systems. However, several of the benefits only occurred in diseased animals (i.e. diabetic mice), while the healthy control group did not benefit from the treatment.

The benefits reported in human studies are mainly focussed on senescent cell markers. So far, these markers are only hypothesized to translate to clinically meaningful effects. Few benefits had direct clinical relevance, and those were not really convincing. Additionally, 2 out of the 3 clinical studies were in patients with pre-existing disease so there is very limited information on the effect in healthy individuals. The potential risks of D are extensive and well-known through its use in the treatment of cancer. While the clinical trials that used D+Q as a senolytic therapy reported only mild to moderate adverse events, it is of note that the low number of participants in these studies might not deliver a representative result.

Furthermore, the human studies all used different treatment protocols and there is no consensus on the measurement of efficacy in clinical practice. Therefore, until there are more studies showing benefits in humans, a clearer picture of the senolytic-use specific risk profile, and a consensus on a treatment protocol, it seems prudent to avoid the use of D+Q as a senolytic therapy.

To what degree is increased blood flow to the brain the important mechanism mediating the beneficial effects of exercise on memory? Exercise improves memory both in the very short term, and over the long term. This may be as simple as increased blood flow delivering more of the nutrients and signals that spur brain tissue into greater activity, though there are other mechanisms to consider as well. The research here adds evidence for the effect to result from better blood flow to memory-related areas of the brain.

Scientists have collected plenty of evidence linking exercise to brain health, with some research suggesting fitness may even improve memory. But what happens during exercise to trigger these benefits? New research that mapped brain changes after one year of aerobic workouts has uncovered a potentially critical process: Exercise boosts blood flow into two key regions of the brain associated with memory. Notably, the study showed this blood flow can help even older people with memory issues improve cognition, a finding that scientists say could guide future Alzheimer's disease research.

The study documented changes in long-term memory and cerebral blood flow in 30 participants, each of them 60 or older with memory problems. Half of them underwent 12 months of aerobic exercise training; the rest did only stretching. The exercise group showed a 47 percent improvement in some memory scores after one year compared with minimal change in the stretch participants. Brain imaging of the exercise group, taken while they were at rest at the beginning and end of the study, showed increased blood flow into the anterior cingulate cortex and the hippocampus - neural regions that play important roles in memory function.

Evidence is mounting that exercise could at least play a small role in delaying or reducing the risk of Alzheimer's disease. For example, a 2018 study showed that people with lower fitness levels experienced faster deterioration of vital nerve fibers in the brain called white matter. A study published last year showed exercise correlated with slower deterioration of the hippocampus. "Cerebral blood flow is a part of the puzzle, and we need to continue piecing it together. But we've seen enough data to know that starting a fitness program can have lifelong benefits for our brains as well as our hearts."

Link: https://www.utsouthwestern.edu/newsroom/articles/year-2020/exercise-improves-memory-boosts-blood-flow-to-brain.html

Researchers here investigate detailed measures of brain function over time, and correlate them with the level of physical activity. There is plenty of evidence for greater physical activity to slow cognitive decline with age and reduce the risk of dementia. Which of the many mechanisms involved are the most important is an open question: is it as simple as better vascular function to supply the brain with the nutrients it needs, or are more direct effects on neural mechanisms just as relevant?

Although various studies have identified physical activity as a possible primary preventive protective factor for brain health, the mechanisms by which physical activity affect cognitive function are not fully understood. Until recently, it was thought that physical activity was beneficial to brain health by means of reducing the impact of known risk factors, such as cardiovascular and cerebrovascular disease, stroke, or diabetes. However, there is a growing body of literature from human and animal studies that indicates that the benefits may be more direct, involving the promotion of synaptogenesis, neuroplasticity, and growth and survival of neurons, as well as the reduction of inflammation and stress.

The field of cognitive aging is constantly seeking more reliable biomarkers that accurately reflect the brain's functioning. Functional connectivity (FC) is one factor that has been reported to be affected by the aging process. It is thought to reflect typical cognitive changes in aging. Previous literature has documented disruptions in major large-scale networks during aging in the absence of disease; however, these findings have focused mostly on the default mode network (DMN) and its connections to other regions.

In the present study, we examined the longitudinal relationship between FC and self-reported changes in physical activity in community-dwelling older adults. Given that the DMN, the frontal-parietal network (FPN, also known as the central executive network), and the subcortical network (SN) are widely-examined networks that are associated with abilities such as introspection, executive function, and motor function, respectively, we focused our preliminary investigations on connectivity within these three networks.

We found that specific within-person increases in physical activity may track closely with FC. Importantly, there appears to be specificity regarding the regionality of this effect. Our findings suggest that within-person increases in physical activity are specifically associated with greater frontal-subcortical and within-subcortical network synchrony. Increased FC in these networks may further support the positive effect of physical activity on brain health markers.

Link: https://doi.org/10.3389/fnagi.2020.00104

Microglia are immune cells of the brain, analogous to macrophages in the rest of the body. They take on a broad range of tasks: chasing down pathogens; clearing up cell debris and molecular waste; assisting in regeneration and tissue maintenance; assisting neurons in remodeling of synapses. Microglia, like macrophages, can shift between behavior patterns in response to environmental circumstances, such as M1 (inflammatory and aggressive) and M2 (anti-inflammatory and regenerative).

With advancing age, microglia become increasingly inflammatory: this may be the result of too much molecular waste, such as the amyloid-β associated with Alzheimer's disease, it may be the consequence of persistent infections such as herpeviruses, or there may be other reasons connected to the underlying damage of aging, such as the signaling of chronic inflammation started elsewhere. Evidence from animal studies suggests that inflammatory microglia, and particularly senescent microglia, are quite important in the progression of brain aging. Removing the worst offenders via senolytic drugs, or forcing microglia into the anti-inflammatory M2 state via any one of a number of strategies, appears to be beneficial, a potential basis for therapy.

Calorie restriction, eating up to 40% fewer calories while still obtaining optimal nutrient intake, is the most studied of all interventions known to slow aging in laboratory species. Given that it does slow aging overall, it isn't surprising to find it slowing or improving any particular manifestation of aging. This is the case for the prevalence of inflammatory microglia in the brain, as researchers discuss in today's open access paper. Calorie restriction isn't a way to achieve meaningful rejuvenation in humans - it produces a much greater impact on life span in short-lived mammals than in long-lived mammals - but it is nonetheless one of the most reliable and cost-effective interventions when it comes to improving long-term health. That is more a statement on the presently poor state of medicine to treat the causes of aging than it is on the merits of calorie restriction, however. Senolytics to clear senescent cells are the only form of treatment on the very near horizon likely to do better than calorie restriction.

Effect of Caloric Restriction on the in vivo Functional Properties of Aging Microglia

Throughout the lifespan, microglia, the primary innate immune cells of the brain, fulfill a plethora of homeostatic as well as active immune defense functions, and their aging-induced dysfunctionality is now considered as a key trigger of aging-related brain disorders. Recent evidence suggests that both organism's sex and age critically impact the functional state of microglia but in vivo determinants of such states remain unclear. Therefore, we analyzed in vivo the sex-specific functional states of microglia in young adult, middle aged and old wild type mice by means of multicolor two-photon imaging, using the microglial Ca2+ signaling and directed process motility as main readouts.

Our data revealed the sex-specific differences in microglial Ca2+ signaling at all ages tested, beginning with young adults. Furthermore, for both sexes it showed that during the lifespan the functional state of microglia changes at least twice. Already at middle age the cells are found in the reactive or immune alerted state, characterized by heightened Ca2+ signaling but normal process motility whereas old mice harbor senescent microglia with decreased Ca2+ signaling, and faster but disorganized directed movement of microglial processes.

The 6-12 months long caloric restriction (70% of ad libitum food intake) counteracted these aging-induced changes shifting many but not all functional properties of microglia toward a younger phenotype. The improvement of Ca2+ signaling was more pronounced in males. Importantly, even short-term (6-week-long) caloric restriction beginning at old age strongly improved microglial process motility and induced a significant albeit weaker improvement of microglial Ca2+ signaling. Together, these data provide first sex-specific in vivo characterization of functional properties of microglia along the lifespan and identify caloric restriction as a potent, cost-effective, and clinically relevant tool for rejuvenation of microglia.

Stochastic mutational damage to nuclear DNA occurs constantly in the body, and near all of it is quickly repaired. Most unrepaired damage occurs in DNA that isn't used, or the change has only has a small effect on cell metabolism, or occurs in a somatic cell that will replicate only a limited number of times. When mutations occur in stem cells or progenitor cells, however, they can spread widely through tissue, producing a pattern of mutations known as somatic mosaicism. It is thought that this can contribute to the progression of aging via a slowly growing disarray of cellular metabolism, particularly through the spread of more severe damage, such as aneuploidy, missing or additional chromosomes. That said, firm evidence for the size of this effect remains to be produced. Researchers here focus particularly on this more severe chromosomal mosaicism, rather than minor damage.

Somatic chromosomal mosaicism is the presence of cell populations differing with respect to the chromosome complements (e.g. normal and abnormal) in an individual. Chromosomal mosaicism is associated with a wide spectrum of disease conditions and aging. This type of intercellular genomic variations is commonly associated with a wide spectrum of genetic diseases ranging from chromosomal syndromes to complex disorders, but dynamic changes of mosaicism rates produced by the accumulation of somatic mutations (i.e. aneuploidy) seem to be an important cytogenetic mechanism for human aging.

Cytogenetic and cytogenomic studies of normal and pathological aging consistently demonstrate an increase in rates of chromosomal mosaicism and instability in relation to age. After age 60, older ages have been associated with higher rates of chromosomal mosaicism and instability. Thus, this data allows us to hypothesize that external inhibition of age-dependent chromosome instability and a decrease of somatic chromosomal mosaicism rates might be an opportunity for anti-aging therapeutic interventions.

Furthermore, somatic cancer-associated mutations commonly occur in aged human tissues of presumably healthy individuals. It is not surprising inasmuch as chromosomal mosaicism and instabilities are risk factors for cancers. In general, aging-related diseases are commonly mediated by chromosomal instability and/or mosaic aneuploidy. The results of molecular genetic studies of aging correlate with observations on mutation load contribution to limiting or shortening the lifespan. Additionally, there is evidence that inhibiting chromosome instability might underlie successful anti-aging strategies. Thus, genetic instability at chromosomal level involved in human aging and/or lifespan shortening is an intriguing target for lifespan-extension and anti-aging interventions.

Link: https://doi.org/10.1186/s13039-020-00488-0

Bone is a dynamic structure, constantly built up by osteoblasts and torn down by osteoclasts. In youth there is a balance between these two cell types, but the processes of aging cause osteoclast activity to dominate, and thus bones inexorably lose density and strength. Osteoporosis lies at the end of this road. The research community has over the years investigated numerous possible approaches to force balance in the activity of osteoblasts and osteoclasts, and the work here is just one example of many. It is typical of most, in that it doesn't attempt to identify and address root causes, but instead seeks to intervene in signaling and regulatory processes that are disarrayed as a consequence of the underlying damage of aging. This is probably not the best strategy.

With advancing age, osteoclast-induced bone resorption outpaces osteoblast-induced bone deposition, leading to a gradual loss of bone mass. The use of therapeutic agents that inhibit osteoclast activity and differentiation has been proposed as a strategy to prevent osteoporosis and other bone-related diseases. Osteoclast differentiation is induced by macrophage-colony stimulating factor (M-CSF), receptor activator of nuclear factor (NF)-κB ligand (RANKL), and osteoprotegerin. These cytokines are involved in signaling pathways that balance the activities of osteoblasts and osteoclasts to maintain bone mass homeostasis. The monoclonal antibody denosumab is the only RANKL inhibitor currently approved by the FDA, and has been reported to reduce bone turnover and increase bone mineral density (BMD).

Given that plasma proteins include aging-related factors, we hypothesized that aging would dynamically alter the plasma levels of proteins involved in age-related bone loss. We used a proteomic approach to identify plasma proteins that were differentially expressed between young and old mice, and investigated their effects on osteoclasts and osteoblasts. We focused on Cadherin-13 (CDH-13), examining its impact on osteoclast differentiation and bone resorption. Finally, we tested whether intraperitoneal administration of CDH-13 could prevent age-related bone loss in mice.

Our results demonstrated that CDH-13 inhibits osteoclast differentiation by blocking RANKL signaling. Although the underlying molecular mechanisms remain to be elucidated, we speculate that plasma CDH-13 may function as a decoy receptor of RANKL or as a RANK receptor antagonist. We also found that CDH-13 was enriched in the blood of young mice and helped to preserve bone mass by inhibiting RANKL-induced osteoclast differentiation. Multiple circulating factors regulate bone mass. Our results suggested that CDH-13 is an age-related bone factor, and that lower levels of CDH-13 disrupt the balance of bone remodeling and promote age-related bone loss. Since the inhibition of RANKL has long been recognized as a therapeutic strategy for osteoporosis, our findings suggest that CDH-13 could be used as a novel therapeutic molecule to inhibit bone loss.

Link: https://doi.org/10.18632/aging.103184

In today's open access paper, the authors demonstrate a form of vaccination against a surface marker that appears on a subset of senescent T cells that reside in fat tissue, thus directing the rest of the immune system to attack and destroy these cells. There is good evidence for excess fat tissue to result in an increased burden of senescent cells, which disrupt metabolism via the generation of inflammatory signals. A novel branch of medicine is under construction, based on senolytic therapies capable of selectively destroying senescent cells in aged tissues. The growing numbers of senescent cells in older people (and even larger numbers in older obese people) contribute to near all conditions of aging. Removing them has proven to be very beneficial in animal studies, reversing the progression of numerous age-related diseases.

A global, always-on mechanism to remove senescent cells has been shown to improve health and longevity in mice, but is probably not a good idea for human medicine. Senescence is a harmful process only when it runs awry, when senescent cells accumulate over time. Senescent cells are constantly created in a youthful metabolism, and serve useful purposes in suppression of cancer, wound healing, and other processes. They are near all rapidly destroyed, either by the immune system or by programmed cell death mechanisms. Only when they linger are they problematic, as starts to happen with aging. A vaccine that provoked constant, efficient destruction of all senescent cells (if such a thing was possible) would probably negatively impact regenerative capacity, at the very least.

In this case, it is possible to argue that the senescent T cells found in fat tissue, and particularly in excessive fat tissue deposits, serve no useful purpose. More work would need to be done to prove that point, but it is not an unreasonable hypothesis. Other populations of senescent cells may also exhibit distinctive surface markers and consistently harmful behavior, and thus also be good targets for a vaccination approach to therapy. This type of therapy is an interesting proposition, but may ultimately fail the cost-benefit analysis when compared with the much simpler strategy of periodic dosing with a mix of senolytic compounds that kill a sizable fraction of all senescent cells. Whether or not that is the case rather depends on the details, which will emerge over time as the field progresses.

The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice

Senescent cells produce proinflammatory and matrix-degrading molecules, which harm their surrounding nonsenescent cells. Senotherapy targeting for senescent cells is designed to attenuate age-related dysfunction and promote healthy aging and the removal of senescent cells by direct killing, either by apoptotic (senoptosis) or nonapoptotic (senolysis) methods, is an effective serotherapeutic approach. In the genetic model, INK-ATTAC mice, to undergo the inducible elimination of p16Ink4a-expressing cells, these mice in which p16Ink4a-positive senescent cells were eliminated exhibited a long life span and the attenuation of several aging phenotypes in white adipose tissue, the heart, and the kidney.

Senescent cells accumulate in fat in aging, and exercise-mediated reduction as well as genetic clearance improved glucose metabolism or lipotoxicity, respectively. Senescent T cells (referred to as senescence-associated T cells; SA-T cells), defined as CD4+ CD44high CD62Llow PD-1+ CD153+ cells, accumulate in visceral adipose tissues (VAT) in obese individuals and produce proinflammatory cytokines, causing chronic inflammation, metabolic disorders, and cardiovascular diseases. However, it is still unknown whether the selective depletion of senescent T cells can attenuate the age-related pathological changes.

Here, we show the long-lasting effect of using CD153 vaccination to remove senescent T cells from high-fat diet (HFD)-induced obese C57BL/6J mice. We administered a CD153 peptide-KLH (keyhole limpet hemocyanin) conjugate vaccine with and confirmed an increase in anti-CD153 antibody levels that was sustained for several months. After being fed a HFD for 10-11 weeks, adipose senescent T cell accumulation was significantly reduced in the VAT of vaccinated mice, accompanied by improved glucose tolerance and insulin resistance. A complement-dependent cytotoxicity (CDC) assay indicated that the mouse IgG2 antibody produced in the vaccinated mice successfully reduced the number of senescent T cells.

Here, researchers discuss data that sheds light on the way in which age-related declines in autophagy, related mitochondrial dysfunction due to impairment of mitochondrial autophagy, and decline of the immune system might interact with one another. With advancing age, the immune system becomes less capable but ever more overactive, constantly in a state of inflammation without resolution. The evidence here suggests a progressive failure to remove damaged mitochondria to be a contributing cause of that chronic inflammation, at least in a subset of T cells of the adaptive immune system. It isn't completely settled that mitochondrial autophagy is involved, however.

The aging organism develops a chronic state of initially smoldering and then progressively overt inflammation that contributes to the aging process and thus has been nicknamed "inflammaging". A recent paper reveals that purified CD4+ T lymphocytes from healthy, lean, older (57-68 years) donors produce more TH17-associated/supportive cytokines (IL-6, IL-17A, IL-17F, IL-21, and IL-23) than cells from younger (28-38 years) subjects - a TH17-linked cytokine hyperproducer phenotype (TH17-CHP).

The overarching cause of TH17-CHP appears to be reduced autophagy of mitochondria, which compromises mitochondrial turnover and quality control, as indicated by an increase in mitochondrial mass, an increase in the proton leak, and a reduction in the mitochondrial inner transmembrane potential. In addition, mitochondria contained in CD4+ T cells from older donors exhibited an enhanced basic and maximal oxygen consumption, correlating with reduced glycolytic lactate production, enhanced production of reactive oxygen species (ROS). Conversely, knockdown of the essential autophagy gene ATG3 (but not that of PINK1, a gene specifically involved in mitophagy) inhibited autophagy in CD4+ T cells from younger subjects, inducing TH17-CHP similar to the one spontaneously found in CD4+ T cells from older donors.

Altogether, these results have important conceptual and clinical implications at several levels. They suggest yet another causal link between "normal" aging and deficient autophagy involving a vicious cycle in which aging causes an autophagy defect that then aggravates the aging phenotype. Here, it appears that aging compromises autophagy in CD4+ T lymphocytes to stimulate the secretion of several pro-inflammatory interleukins, thus contributing to inflammaging. However, it remains to be determined in preclinical experiments, in mouse models, whether a selective autophagy (or mitophagy) defect solely affecting CD4+ cells would be sufficient to cause TH17-CHP in vivo and accelerate the aging process. As it stands, it appears that autophagy has rather broad anti-inflammatory effects, notably by avoiding the spill of mitochondrial or nuclear DNA into the cytoplasm (to avoid activation of the cGAS/STING pathway) or by inhibiting excessive activation of the NLRP3 inflammasome.

Link: https://doi.org/10.1016/j.cmet.2020.04.016

Much of the comparative biology of aging involves study of long-lived mammals in an attempt to understand which mechanisms determine species longevity. It is possible that a better understanding of this biochemistry might form the basis for therapies, though this is by no means guaranteed. It is quite possible that mechanisms of species longevity will be very difficult to move between species, or to influence in another species without negative consequences. The past few decades of research into mimicking the beneficial responses to exercise and calorie restriction well illustrate that reworking the engines of metabolism is a very challenging endeavor. Few inroads have been made despite enormous effort and expenditure. This is one of many reasons as to why I favor the damage repair approach: don't try to engineer a better metabolism, keep the one we have, and repair the forms of damage that impair it with age.

One important question in aging research is how differences in genomics and transcriptomics determine the maximum lifespan in various species. Despite recent progress, much is still unclear on the topic, partly due to the lack of samples in non-model organisms and due to challenges in direct comparisons of transcriptomes from different species. The novel ranking-based method that we employ here is used to analyze gene expression in the gray whale and compare its de novo assembled transcriptome with that of other long- and short-lived mammals.

Gray whales are among the top 1% longest-lived mammals. Despite the extreme environment, or maybe due to a remarkable adaptation to its habitat (intermittent hypoxia, Arctic water, and high pressure), gray whales reach at least the age of 77 years. In this work, we show that long-lived mammals share common gene expression patterns between themselves, including high expression of DNA maintenance and repair, ubiquitination, apoptosis, and immune responses. Additionally, the level of expression for gray whale orthologs of pro- and anti-longevity genes found in model organisms is in support of their alleged role and direction in lifespan determination. Remarkably, among highly expressed pro-longevity genes many are stress-related, reflecting an adaptation to extreme environmental conditions.

The conducted analysis suggests that the gray whale potentially possesses high resistance to cancer and stress, at least in part ensuring its longevity. This new transcriptome assembly also provides important resources to support the efforts of maintaining the endangered population of gray whales.

Link: https://doi.org/10.1101/754218

Both hair graying and hair loss with age are well researched topics, but there remains considerable uncertainty over which of the possible mechanisms involved are the most relevant, or most useful as targets for therapy. This state of affairs is well illustrated by the feverish interest that attends any possible advance towards reversing male and female pattern baldness. Also the sizable marketplaces devoted to treatments that work poorly, if at all.

Today's trial results are interesting, in that I don't recall seeing stem cell factors being used topically before. There is of course a great deal of nonsense and unscientific endeavor underway related to skin aging, so possibly I'll find those projects if I look at that end of the industry. As a general rule the skin is good at keeping near everything out; one shouldn't expect topical administration to work just because cells and tissues react in a certain way to signals either in vivo or in vitro. The signals secreted by the types of stem cell most often used in therapies are well known to reduce inflammation for a period of time: the cells die quite quickly, but their signals have an effect on native cells that can last for months. Unfortunately this has far less reliable effects on regeneration.

Nonetheless, researchers here offer results from a small trial of topical application of factors derived from stem cells, suggesting that it spurs hair regrowth to a large enough degree to be interesting. Whether this holds up in larger trials remains to be seen.

Clinical trial shows ability of stem cell-based topical solution to regrow hair

Androgenetic alopecia (AGA) - commonly known as male-pattern baldness (female-pattern baldness in women) -- is a condition caused by genetic, hormonal, and environmental factors. It affects an estimated 50 percent of all men and almost as many women older than 50. Adipose tissue-derived stem cells (ADSCs) secrete several growth hormones that help cells develop and proliferate. According to laboratory and experimental studies, growth factors such as hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) increase the size of the hair follicle during hair development.

The team recruited 38 patients (29 men and nine women) with AGA and assigned half to an intervention group that received the stem cell constituent extract (ADSC-CE) topical solution and half as a control group that received a placebo. Twice daily, each patient applied the ADSC-CE topical solution or placebo to their scalp using their fingers. "At the end of 16 weeks, the group that received the ADSC-CEs had a significant increase in both hair count and follicle diameter. Our findings suggest that the application of the ADSC-CE topical solution has enormous potential as an alternative therapeutic strategy for hair regrowth in patients with AGA, by increasing both hair density and thickness while maintaining adequate treatment safety. The next step should be to conduct similar studies with large and diverse populations in order to confirm the beneficial effects of ADSC-CE on hair growth and elucidate the mechanisms responsible for the action of ADSC-CE in humans."

A randomized, double-blind, vehicle-controlled clinical study of hair regeneration using adipose-derived stem cell constituent extract in androgenetic alopecia

Accumulating evidence suggests that adipose-derived stem cell constituent extract (ADSC-CE) helps hair regrowth in patients with androgenetic alopecia (AGA). However, the effects of ADSC-CE have not been demonstrated in a randomized, double-blind, vehicle-controlled clinical trial. In this randomized, double-blind, vehicle-controlled clinical trial, 38 patients (29 men) with AGA were assigned to an intervention group (IG), with twice-daily self-application of the ADSC-CE topical solution over the scalp with fingers, or to a control group (CG). Changes in hair count and thickness from the baseline at 16 weeks were evaluated using a phototrichogram.

Overall, 34 (89%) patients (mean age, 45.3 years) completed the study. The phototrichogram at week 8 showed more increase in hair count in the IG than in the CG, and intergroup differences in the change of hair count remained significant until week 16 with overall changes of 28.1% vs 7.1%, respectively. Similarly, a significant improvement in hair diameter was observed in the IG (14.2%) after 16 weeks when compared with hair diameter in the CG (6.3%). Our findings suggest that the application of the ADSC-CE topical solution has enormous potential as an alternative therapeutic strategy for hair regrowth in patients with AGA, by increasing both hair density and thickness while maintaining adequate treatment safety.

While ageism certainly exists, I've never really liked the use of ageism as an explanation for the lack of progress towards rejuvenation therapies, and this in an era of biotechnology in which all the fundamental puzzle pieces exist and just need to be joined together. What might be seen as ageism is perhaps just one narrow aspect of the broader truth that, beyond immediate friends and family, most people do not focus all that much on concern for others. Some of those others are old, but it isn't that they are old that produces the lack of concern. It is simply not a common trait to have strong concerns for entire classes of people that one doesn't interact with all that much. If explaining lack of progress towards treatments for aging in terms of ageism, then one also has to explain why research into age-related diseases such as cancer is so widely supported - and so on for any number of other lines of medical development.

Ageism is a reality in western societies and current views of older people are too often tinged with false beliefs and prejudices. Public authorities often consider older adults to be a burden rather than an integral segment of the population whose members must be supported. Older adults are rarely given a voice and are seldom considered when making decisions. The media has a considerable role in the propagation of ageist stereotypes and negative attitudes towards older adults, particularly in times of crisis when age is not a relevant factor. The COVID-19 pandemic has accentuated the exclusion of and prejudice against older adults. The current crisis highlights a disturbing public discourse about aging that questions the value of older adults' lives and disregards their valuable contributions to society.

Even though COVID-19 mortality rates are higher in older adults compared to other age groups, our concern is that age is being conflated with frailty and co-morbidity, which are likely to be the more important factors associated with mortality. Social media highlights older adults who sacrifice their own lives so that ventilators can be used for someone younger. When medical equipment, and hospital capacity becomes scarce, care providers may be faced with the ethical decisions about whose life takes priority and age may become a deciding factor. The United States have formally adopted the Ventilator Allocation Guidelines whereby "age may be considered as a tie-breaking criterion in limited circumstances". This may lead people to believe that an older person's life may be less valuable than that of someone younger. What will be the cost to society of the sacrificed lives of older adults?

As concerned advocates and researchers interested in aging, it is our opinion that we should be aware of and try to reduce the ageist views being propagated during COVID-19. Higher mortality rates for any group, including older adults, have devastating consequences. It's not just the preventable loss of human lives or strain being placed on our healthcare and social systems, older adults are invaluable members of society. They are a source of generational knowledge and wisdom, they contribute to the workforce in increasing numbers, they volunteer and they are key to the strength of our economies and our families. We cannot afford to be careless about these lost lives because of ageist attitudes. We need to consider what we stand to lose if we let ageism influence how we discuss and treat older adults during and after the COVID-19 pandemic.

Link: https://doi.org/10.1093/ageing/afaa097

HDAC1 is involved in a form of DNA repair, but levels decline with age, as well as in Alzheimer's disease. This leads to a greater accumulation of unrepaired oxidative DNA damage in neurons. Researchers here note that increased activation of HDAC1 appears to improve cognitive function via a reduction in this oxidative DNA damage. An HDAC1 activator drug has been tested as a treatment for dementia, but caused serious side-effects. Better compounds or other approaches may be able to obtain similar benefits without the harms.

There are several members of the HDAC family of enzymes, and their primary function is to modify histones - proteins around which DNA is spooled. These modifications control gene expression by blocking genes in certain stretches of DNA from being copied into RNA. In 2013, researchers linked HDAC1 to DNA repair in neurons. In the current paper, the researchers explored what happens when HDAC1-mediated repair fails to occur. To do that, they engineered mice in which they could knock out HDAC1 specifically in neurons and another type of brain cells called astrocytes.

For the first several months of the mice's lives, there were no discernable differences in their DNA damage levels or behavior, compared to normal mice. However, as the mice aged, differences became more apparent. DNA damage began to accumulate in the HDAC1-deficient mice, and they also lost some of their ability to modulate synaptic plasticity - changes in the strength of the connections between neurons. The older mice lacking HCAC1 also showed impairments in tests of memory and spatial navigation.

The researchers found that HDAC1 loss led to a specific type of DNA damage called 8-oxo-guanine lesions, which are a signature of oxidative DNA damage. Studies of Alzheimer's patients have also shown high levels of this type of DNA damage, which is often caused by accumulation of harmful metabolic byproducts. The brain's ability to clear these byproducts often diminishes with age. An enzyme called OGG1 is responsible for repairing this type of oxidative DNA damage, and the researchers found that HDAC1 is needed to activate OGG1. When HDAC1 is missing, OGG1 fails to turn on and DNA damage goes unrepaired. Many of the genes that the researchers found to be most susceptible to this type of damage encode ion channels, which are critical for the function of synapses.

Several years ago, researchers screened libraries of small molecules in search of potential drug compounds that activate or inhibit members of the HDAC family. In the new paper, researchers used one of these drugs, called exifone, to see if they could reverse the age-related DNA damage they saw in mice lacking HDAC1. The researchers used exifone to treat two different mouse models of Alzheimer's, as well as healthy older mice. In all cases, they found that the drug reduced the levels of oxidative DNA damage in the brain and improved the mice's cognitive functions, including memory. Exifone was approved in the 1980s in Europe to treat dementia but was later taken off the market because it caused liver damage in some patients. Researchers are optimistic that other, safer HDAC1-activating drugs could be worth pursuing as potential treatments for both age-related cognitive decline and Alzheimer's disease.

Link: https://news.mit.edu/2020/aging-neurons-dna-damage-0518

Today's open access research implicates an imbalance of mitochondrial dynamics in the direction of too much mitochondrial fission in the age-related chronic inflammation observed in endothelial cells of the cardiovascular system. Every cell carries a herd of hundreds of mitochondria, the distant descendants of symbiotic bacteria now integrated as cellular components. The primary task of mitochondria is to generate adenosine triphosphate (ATP), a chemical energy store used to power cellular operations, but they are involved in many core cellular processes. Mitochondria are removed when damaged by the quality control mechanism of mitophagy, and replicate by fission in order to make up their numbers. Mitochondria are very dynamic structures: they pass around component parts, fuse together, and split apart constantly.

A balance between mitochondrial fission and fusion is necessary for optimal cellular function. A sizable portion of the age-related decline in mitochondrial function may be due to an imbalance in the direction of excessive fusion, leading to large mitochondria that become worn and damaged but are resistant to recycling via mitophagy. The proximate cause of this issue appears to be changes in gene expression and protein levels, such as NAD+, or MFF and PUM2, but links to deeper, more fundamental causes of aging remain to be established in a concrete way. It isn't as simple as just a matter of too much fusion, however, as the research here illustrates. Certainly, changes in mitochondrial dynamics are involved in a number of important issues in aging, and imbalance in either direction can be problematic.

Researchers Uncover Link between Blood Vessel Inflammation and Malfunctioning Cellular Powerhouses

The vast majority of cells in the human body contain tiny power plants known as mitochondria that generate much of the energy cells use for day-to-day activities. Like a dynamic renewable resource, these little power plants are constantly dividing and uniting in processes called fission and fusion. The balance between fission and fusion is critical for health - especially cardiovascular health. Now, scientists have uncovered a novel mechanism by which abnormalities in mitochondrial fission in endothelial cells - the cells that line the inner surface of blood vessels - contribute to inflammation and oxidative stress in the cardiovascular system. They further show how the fission-fusion balance can be stabilized to lower inflammation using salicylate, the main active ingredient in everyday pain-relieving drugs like aspirin.

In endothelial cells, chronic inflammation causes mitochondria to become smaller and fragmented. This damaging process is mediated by a molecule known as dynamin-related protein 1 (Drp1). Normally, Drp1 plays a helpful role in maintaining fission-fusion balance. When cells are stressed by inflammation, however, it steps up fission activity, resulting in mitochondrial fragmentation. Researchers stimulated inflammatory pathways that produced mitochondrial fragmentation. They then examined the effects of blocking Drp1 activity and expression. These experiments showed that in cells, Drp1 inhibition suppresses mitochondrial fission, NF-κB activation, and inflammation. Reductions in fission and inflammation were also observed in cells following NF-κB inhibition, as well as in follow-up studies in mice genetically engineered to have less Drp1.

The researchers next determined whether the anti-inflammatory drug salicylate could also reduce mitochondrial fragmentation. Salicylate works by blocking the activity of multiple inflammatory molecules, including NF-κB. As anticipated, in mice, treatment with salicylate attenuated inflammation and mitochondrial fragmentation via its effects on NF-κB and downstream pathways.

Mitochondrial Fission Mediates Endothelial Inflammation

Endothelial inflammation and mitochondrial dysfunction have been implicated in cardiovascular diseases, yet, a unifying mechanism tying them together remains limited. Mitochondrial dysfunction is frequently associated with mitochondrial fission/fragmentation mediated by the GTPase Drp1 (dynamin-related protein 1). Nuclear factor (NF)-κB, a master regulator of inflammation, is implicated in endothelial dysfunction and resultant complications. Here, we explore a causal relationship between mitochondrial fission and NF-κB activation in endothelial inflammatory responses.

In cultured endothelial cells, TNF-α (tumor necrosis factor-α) or lipopolysaccharide induces mitochondrial fragmentation. Inhibition of Drp1 activity or expression suppresses mitochondrial fission, NF-κB activation, vascular cell adhesion molecule-1 induction, and leukocyte adhesion induced by these proinflammatory factors. Moreover, attenuations of inflammatory leukocyte adhesion were observed in Drp1 deficient mice. Intriguingly, inhibition of the canonical NF-κB signaling suppresses endothelial mitochondrial fission. Mechanistically, NF-κB p65/RelA seems to mediate inflammatory mitochondrial fission in endothelial cells. In addition, the classical anti-inflammatory drug, salicylate, seems to maintain mitochondrial fission/fusion balance against TNF-α via inhibition of NF-κB.

In conclusion, our results suggest a previously unknown mechanism whereby the canonical NF-κB cascade and a mitochondrial fission pathway interdependently regulate endothelial inflammation.

As for other aspects of metabolic regulation, circadian rhythm becomes increasingly disrupted with age. Researchers here provide evidence for falling NAD+ levels to be a proximate cause of this issue. NAD+ is important in the core activity of mitochondria, generation of energy store molecules to power cellular operations, but also acts on numerous other processes in the cell. Unfortunately the various mechanisms of synthesis and recycling of NAD+ falter as tissues age, though it is an open question as to how much of this is a matter of failing to maintain fitness versus more inexorable processes of aging. Data suggests that exercise programs in older individuals can do just as well, if not better, than approaches based on providing NAD+ precursors such as nicotinamide riboside as supplements.

Cellular levels of NAD+ decline with ageing, and boosting NAD+ production by administration of its precursors promotes youthful behavioural and physiological functions in mice. To investigate the role of NAD+ in circadian gene expression in mice, the authors gave mice drinking water that was supplemented with NAD+ precursors for 4 months and analysed circadian gene expression in the liver. This revealed that the expression pattern of approximately half of circadian-regulated hepatic genes changed upon NAD+ increase.

NAD+ is a cofactor for sirtuin deacetylases, which are known to promote healthspan and lifespan. Sirtuin 1 (SIRT1) regulates circadian rhythms by binding to the core clock complex - comprising heterodimeric circadian transcription activator CLOCK-BMAL1 and its repressor PER2 - and driving PER2 deacetylation and subsequent degradation. Liver-specific Sirt1 knockout abrogated the changes in hepatic circadian gene expression that were observed when NAD+ levels were increased.

Next, the authors found that in the liver of old mice, chromatin occupancy of BMAL1 was decreased, which coincided with increased PER2 levels and decreased amplitude of circadian gene oscillations. Administration of NAD+ precursor to the old mice for 6 months restored BMAL1 chromatin binding and function to levels observed in young animals. In addition, late-night locomotor activity, normally reduced in old mice, was restored to youthful levels with NAD+ precursor administration. In summary, elevating NAD+ has the capacity to reverse ageing-associated dysfunction of circadian rhythms.

Link: https://doi.org/10.1038/s41580-020-0254-8

Kingsley Advani is one of the more active angel investors in the growing longevity industry. This is still a young industry, and like many of people involved, whether as entrepreneurs or investors, Advani is motivated more by an interest in achieving progress in medical technology than in a return on investment. Though of course, investors who ignore that second point tend not to remain investors for all that long.

What do Juvenescence, Oisín Biotechnologies, Volumetric, and GEn1E Lifesciences have in common? Yes, they are all companies that fit squarely in the burgeoning Longevity sector, but they are also companies invested in by Kingsley Advani, a US-based British investor who has made the extension of human life one of his key investment categories. In addition to investing in more than 50 companies, Advani is also a financial supporter of non-profit longevity organisations including SENS Research Foundation, Methuselah Foundation, and the National University of Singapore.

I think that Juvenescence have a very sensible approach, they are very well capitalised and they have multiple shots on goal. They have companies in their portfolio that are working on areas like tissue regeneration, like LyGenesis, who are using lymph nodes as bioreactors, and companies like Insilico Medicine that are using deep learning for drug discovery. So they have a pretty wide range of shots on goal."

"I invest in the longevity industry for the impact, because if you could extend the healthy lives of eight billion people, then it's really a noble act. Secondly, I felt that longevity was underserved in terms of investment - a majority of these companies are privately funded and there's a lack of attention from government, so I felt there was a gap in terms of private investment. I want to increase volume of investment in longevity companies and so I've been educating more private investors about longevity."

Link: https://www.longevity.technology/the-next-generation-of-longevity-investment/

I am a few months late in noting this: videos from last year's Longevity Forum, one of the events in the Longevity Week held in London in November 2019, in what now seems an entirely different world, were posted online earlier this year. The Longevity Forum is organized by Jim Mellon and allies, a part of his diverse efforts to advance the growth of a longevity-focused medical industry capable of turning back aging and significantly lengthening healthy life spans.

The Forum is focused on non-profits, regulatory concerns, and government policy rather than on industry, but there are nonetheless interesting presentations. The purpose here is to help educate decision makers and the public as to what researchers and the longevity industry is working on, the plausible emergence of much longer lives in the near future, and to suggest that some thought should go into smoothing the path to the clinic ahead of time.

This is a big tent sort of a venture, and you'll find people working on rejuvenation therapies rubbing shoulders with those who limit their considerations to exercise programs for seniors. Then throw into the mix noted non-profit fundraisers, policy makers, and other interested parties. I've noted a couple of the presentation videos; there are others, so by all means take a look at the full list.

Panel: How can the UK add five years of healthy lifespan by 2030

This panel will explore the recent advances in pro-longevity therapies, including small molecules, stem cells, regenerative medicine , microbiome and gene therapy. All of these are, to varying degrees, in human trials and the combination of these exciting developments and the fact that ageing pathways have been proven to be malleable, make the bioengineering of human beings to live longer and more robustly a strong likelihood, rather than an historically improbable aspiration. Indeed, it is clear that the science of biogerontology is rapidly catching up with the desire of most of us to live longer and in better health.

Aubrey de Grey: Scientists, check, Investors, check, Next up, policy makers

Aubrey de Grey delivers a keynote on the next steps for longevity for policy makers. Dr Aubrey de Grey is a biomedical gerontologist based in Mountain View, California, USA, and is the Chief Science Officer of SENS Research Foundation, a California-based 501(c)(3) biomedical research charity that performs and funds laboratory research dedicated to combating the ageing process.

Scientists here expand upon prior research indicating that longer-lived species tend to exhibit certain types of sequence difference in the tumor suppressor gene p53 - a gene also involved in many other processes relevant to aging. One might compare this with past studies that examine the number of copies of this gene in long-lived, larger species. Elephants have many copies of p53, for example, which might go long way towards explaining why they don't exhibit higher cancer rates despite their great size, and thus greater number of cells.

The p53 protein is a well-known tumor suppressor and TP53 is the most often mutated gene in human cancers. On the cellular level, decreased p53 functionality is essential for cellular immortalization and neoplastic transformation. However, the role of variations in the p53 amino acid sequence on the organism level has not been studied systematically. Here, we presented an in-depth correlation analysis manifesting the dependencies between p53 variations and organismal lifespan to address the role of p53 in longevity. To date, p53 expression has been detected in all sequenced animals from unicellular Holozoans to vertebrates, with the lone exception of the immortal Turritopsis jellyfish.

The results from Protein Variation Effect Analyzer show that the variability in lifespan among closely related species correlates with specific p53 variations. Long-lived organisms are characterized by in-frame deletions, changes, insertions or specific substitutions in the p53 sequence. It is likely that the changes imposed on p53 in long-lived species enable p53 to interact with different multiple protein partners to induce gene expression programs varying from those induced in species with relatively normal lifespan.

We can anticipate that these gene expression programmes would enable following changes: 1. more efficient tissue repair through autophagy, 2. loss of senescence, 3. enhanced clearance of senescent cells by the immune system, 4. enhanced regulation of intracellular reactive oxygen species (ROS) levels 5. improved resistance of mitochondria to ROS-induced damage or 6. loss of immune senescence that occurs in humans with age. All of the mentioned processes have been previously described as significantly contributing to longevity. Thus, long-lived organisms apparently have a different mechanism of protection against cancer and their lifespan is not limited by somatic cell senescence caused by active p53 protein, which is the case for other species with shorter lifespan as mentioned above.

We inspected TP53 gene sequences in individual species of phylogenetically related organisms that show different aging patterns. We discovered novel correlations between specific amino acid variations in p53 and lifespan across different animal species. In particular, we found that species with extended lifespan have characteristic amino acid substitutions mainly in the p53 DNA binding domain that change its function. These findings lead us to propose a theory of longevity based on alterations in TP53 that might be responsible for determining extended organismal lifespan.

Link: https://doi.org/10.1101/2020.05.06.080200

Naked mole-rats live nine times as long as similarly sized rodents, and are near immune to cancer. Researchers have for some years investigated the biochemistry of this species, in search of mechanisms that might be applied to improve health and longevity in other mammals, or form the basis for cancer therapies. Teams have looked into many different areas: mitochondrial function; better DNA repair; a greatly attenuated senescence-associated secretory phenotype; more efficient operation of cancer-suppression genes; and a heavier form of hyaluronan. Researchers here show that this heavier form of hyaluronan is protective of cells, and can produce this protective effect in human cells as well as naked mole-rat cells.

The longest-living rodent, the naked mole-rat (NMR) (Heterocephalus glaber), has a maximum lifespan of more than 30 years, which is fivefold greater than predicted by body mass. NMR does not show increase in mortality rates for at least 18 years, and seems to be protected from age-related deterioration such as metabolic decline, diabetes, and osteoporosis. These features indicate that NMR has evolved efficient anti-aging mechanisms. However, although NMR is increasingly appreciated as a model for aging research, how they resist aging processes remains largely unknown.

An important NMR-specific anti-cancer mechanism is early contact inhibition (ECI). Cultured NMR fibroblasts are hypersensitive to contact inhibition and stop proliferating at relatively low cell density in a hyaluronan (HA)-dependent manner. HA plays a role in supporting tissue structure and regulating cellular signaling pathways depending on its polymer length. Dynamic regulation of the amount and polymer length of HA is implicated in diverse biological processes including cell proliferation, cell migration, and inflammation. In healthy tissues, most of HA is of high-molecular-mass (HMM-HA). In pathological circumstances, significant fragmentation of HA occurs, giving rise to low-molecular-mass HA. NMR produces very-high-molecular-mass hyaluronan (vHMM-HA), much longer than HA in other mammalian species. However, it is still not clear whether HA of exceptionally high polymer length is functionally different from regular HMM-HA.

The observations that HA exhibits polymer length-dependent cytoprotective effect and that long-lived NMR produces vHMM-HA lead to a hypothesis that additional polymer length of NMR-HA confers superior cytoprotection that could contribute to the NMR's longevity. Here, we show that vHMM-HA has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner.

The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.

Link: https://doi.org/10.1038/s41467-020-16050-w

Today's open access paper is a review of what is known of the role of cellular senescence in lung disease. With the development of senolytic therapies that can selectively destroy senescent cells, all conditions in which senescent cells contribute meaningfully to pathology may soon be effectively treated. Senescent cells accumulate with age in all tissues, and while never a sizable fraction of all cells, even a comparatively small number of senescent cells can cause chronic inflammation and tissue dysfunction. They secrete a mix of inflammatory signals, growth factors, and other molecules that has a sizable effect on the behavior of surrounding cells. In the short term, this behavior is a necessary part of wound healing and cancer suppression, among other activities, but when sustained over the long term, this contributes to the degeneration and diseases of aging.

Taken in the broader context of medical research as a whole, senescence is still poorly mapped, and its role in all too many conditions is not explored in any detail. There is only so much research funding, and only so many research teams. The hundreds of age-related conditions and scores of different tissues in the body are being explored with some sense of prioritization, but a great deal of work remains to be accomplished. The lung in an organ for which the role of cellular senescence in disease been more extensively investigated in recent years, largely because senescent cells are implicated in fibrosis, and fibrotic lung diseases have no truly effective treatments at this time. One of the first human trials of a senolytic therapy targeted idiopathic pulmonary fibrosis, and further, some very interesting animal studies have examined the more general decline of lung function with age, and its reversal through senolytic therapy.

Cellular Senescence in the Lung: The Central Role of Senescent Epithelial Cells

It is thought that cellular senescence contributes to developmental processes including promoting remodeling, inflammation, infectious susceptibility, and angiogenesis as well as fundamental processes, such as wound healing and tissue regeneration. Herein, senescent cells which fulfilled their action are removed from the interfered tissue via infiltrating immune cells. However, if senescent cells persist, these cells might foster age- and disease-associated physiological dysfunction particularly through their progressively changing secretory profile. With this respect, cellular senescence is now considered an important driving force for the development of chronic lung pathologies, particularly chronic inflammation observed in lungs of aging patients and of patients suffering from asthma, chronic obstructive pulmonary disease, or pulmonary fibrosis. The accumulation of senescent cells in lungs has disadvantageous consequences. Understanding the mechanisms driving induction of cellular senescence as well as the mechanisms mediating pathology-promoting effects of senescence may offer new treatment strategies for chronic lung diseases.

Age-related changes in lung morphology include enlargement of small airways and a decreased alveolar surface tension, finally leading to a compliant distensible lung. Furthermore, senescent cells with increased senescence-associated secretory phenotype (SASP) secretion accumulate with age in adult lungs; these cells exert autocrine and paracrine effects resulting in increased inflammation, induced stem cell dysfunction, and/or senescence of neighboring cells. Most importantly, the age-related increase in senescent lung cells, together with 'immune senescence', namely the lack of inflammatory cells to respond to SASP, result in an ineffective or slowed clearance of senescent cells, a progressively altered local environment, and subsequently tissue aging or development of age-related diseases.

Considerable in vitro and preclinical in vivo data support a deleterious impact of senescence on vascular endothelial cells finally resulting in the failure of the endothelium to perform its normal, physiologic functions. It has been demonstrated that chronic clearance of senescent cells with senolytic drugs (e.g., dasatinib or quercetin), that selectively induce death of senescent cells or genetic clearance of p16-expressing endothelial cells, improves vascular phenotypes.

Repetitive injury, especially to the pulmonary epithelium, is considered a central factor in the development of various lung diseases. Herein, the senescence of the respiratory epithelium is regarded as a central process for the initiation and progression of related lung diseases, particularly in pulmonary fibrosis and experimental lung fibrosis models. Human lung tissues from lung fibrosis (idiopathic pulmonary fibrosis, IPF) patients were shown to harbor numerous senescent epithelial cells as revealed by prominent SA-β-gal and p16 staining. IPF related epithelial senescence was closely associated with the SASP factors IL-1β, IL-6, IL-8 and TNF-α, which were already correlated with pulmonary fibrogenesis. Therefore, the current hypothesis is that alveolar epithelial injury imposed on senescent epithelial cells leads to aberrant wound healing and the secretion of high levels of growth factors and chemokines that foster the activation of adjacent cells, including endothelial cells and fibroblasts, and fibrogensis.

In a preclinical model of radiation-induced pneumopathy, clearance of senescent cells with a senolytic drug (ABT-263) efficiently reduced senescent cells and reversed pulmonary fibrosis. This, of course, would even limit the diminishing epithelial regenerative capacity, as well as associated SASP-mediated effects on adjacent lung cells as a central aspect in the development of lung injury. Therefore, targeting particularly senescent lung epithelial cells was suggested as a promising option for pulmonary fibrosis. Moreover, treatment of irradiated mice with ABT-263 almost completely reversed pulmonary fibrosis, even when the initiation of ABT-263 treatment was delayed until fibrosis was established. This means that unlike other known radiation protectants and mitigators, which were usually needed to be applied before or shortly after radiotherapy, senolytic drugs such as ABT-263 have the potential to be used as an effective, novel treatment of radiation-induced side complications such as inflammation and fibrosis, even after the lung injury develops into a progressive disease.

Researchers here report on the application of various forms of exercise program to aged rats, followed by observing the effects on age-related cognitive impairment and related changes in the biochemistry of the brain. Wnt signaling, connected to a range of important cellular processes related to regeneration and tissue maintenance, is noted as one of the important pathways altered by exercise. This isn't any great secret, I should say. Wnt signaling is well studied, and regenerative therapies based on manipulation of Wnt signaling are at a fairly advanced stage of development. Samumed has treatments in late stage clinical trials, for example.

Down-regulated Wnt signaling is involved in brain aging with declined cognitive capacity due to its modulation on neuronal function and synaptic plasticity. However, the molecular mechanisms are still unclear. In the present study, the naturally aged rat model was established by feeding rats from 6 months old to 21 months old. The cognitive capacity of aged rats was compared with young rats as the controls and the aged rats upon 12-week exercise interventions including treadmill running, resistance exercise, and alternating exercise with resistance exercise and treadmill running. Wnt signaling was examined in hippocampal tissues of the rats from different groups.

Results indicated that the expression of Dickkopf-1 (DKK-1) as an antagonist of Wnt signal pathway, the activation of GSK-3β, and the hyperphosphorylated Tau were markedly increased as the extension of age. Meanwhile, higher phosphorylated β-catenin promoted neuronal degradation of aged rats. In contrast, three kinds of exercise interventions rescued the abnormal expression of DKK-1 and synaptophysin in hippocampal tissues of the aged rats. In particular, 12-week treadmill running suppressed DKK-1 up-regulation, GSK-3β activation, β-catenin phosphorylation, and hyperphosphorylated Tau. In addition, the down-regulated PI3K/AKT and Wnt signal pathways were observed in aged rats, but could be reversed by resistance exercise and treadmill running. Moreover, the increased Bax and reduced Bcl-2 levels in hippocampal tissues of aged rats were also reversed upon treadmill running intervention.

Taken together, down-regulated Wnt signaling suppressed PI3K/Akt signal pathway, aggravated synaptotoxicity, induced neuron apoptosis, and accelerated cognitive impairment of aged rats. However, exercise interventions, especially treadmill running, can attenuate their brain aging process via restoring Wnt signaling and corresponding targets.

Link: https://doi.org/10.3389/fnagi.2020.00105

The paper here offers a good overview of recent research and development aimed at improving the effectiveness of vaccines in old people. Vaccines are only poorly effective in the old because of the age-related decline of the immune system. A great deal of effort, with only some success, has gone into trying to improve vaccine effectiveness in older populations. Even if tinkering with vaccines boosts the percentage of patients who exhibit an immune response, however, that response is always going to be more anemic than that of a younger person, given the effects of aging on the immune system. This time and funding would perhaps be better directed towards ways to reverse the decline of the immune system, rather than towards the discovery of ever more complex ways of provoking the age-impaired immune system into a response.

Infectious diseases are a major cause for morbidity and mortality in the older population. Demographic changes will lead to increasing numbers of older persons over the next decades. Prevention of infections becomes increasingly important to ensure healthy aging for the individual, and to alleviate the socio-economic burden for societies. Undoubtedly, vaccines are the most efficient health care measure to prevent infections. Age-associated changes of the immune system are responsible for decreased immunogenicity and clinical efficacy of most currently used vaccines in older age. Efficacy of standard influenza vaccines is only 30-50% in the older population.

Several approaches, such as higher antigen dose, use of MF59 as adjuvant and intradermal administration have been implemented in order to specifically target the aged immune system. The use of a 23-valent polysaccharide vaccine against Streptococcus pneumoniae has been amended by a 13-valent conjugated pneumococcal vaccine originally developed for young children several years ago to overcome at least some of the limitations of the T cell-independent polysaccharide antigens, but still is only approximately 50% protective against pneumonia. A live-attenuated vaccine against herpes zoster, which has been available for several years, demonstrated efficacy of 51% against herpes zoster and 67% against post-herpetic neuralgia. Protection was lower in the very old and decreased several years after vaccination.

Recently, a recombinant vaccine containing the viral glycoprotein gE and the novel adjuvant AS01B has been licensed. Phase III studies demonstrated efficacy against herpes zoster of approx. 90% even in the oldest age groups after administration of two doses and many countries now recommend the preferential use of this vaccine. There are still many infectious diseases causing substantial morbidity in the older population, for which no vaccines are available so far. Extensive research is ongoing to develop vaccines against novel targets with several vaccine candidates already being clinically tested, which have the potential to substantially reduce health care costs and to save many lives. In addition to the development of novel and improved vaccines, which specifically target the aged immune system, it is also important to improve uptake of the existing vaccines in order to protect the vulnerable, older population.

Link: https://doi.org/10.3389/fimmu.2020.00717

Senescent cells accumulate with age, and this accumulation is an important contributing cause of aging. These errant cells secrete a potent mix of signal molecules that spur chronic inflammation and tissue dysfunction. Animal studies demonstrate that targeted removal of as little as a third of senescent cells in old individuals can produce a sizable reversal of many aspects of aging, as well as of a broad range of age-related diseases. A number of companies have been funded to commercialize senolytic therapies, those capable of selective destruction of senescent cells. Therapies present under development target a range of mechanisms, such as Bcl-2 family influence over apoptosis, and markers, such as p16 and senescence-associated beta-galactosidase.

At this early stage in the development of a senolytics industry, in which comparatively few classes of senolytic treatment exist, any discovery of a novel senolytic mechanism is likely to produce sizable rewards for the organization and researchers involved. Hence many research groups are either digging deeper into the biochemistry of cellular senescence, in search of gold, or screening large numbers of compounds for senolytics that might work in novel ways. Today's open access paper is an example of the second class of initiative. The authors note their discovery of a senolytic small molecule that employs none of the known mechanisms of senolysis, but nonetheless can push senescent cells to self-destruct via apoptosis.

This state of comparative ignorance about how a compound functions is one of the interesting outcomes that can result from screening compound libraries. A team finds a compound that works to kill senescent cells, and they can determine whether or not it works through known mechanisms employed by other senolytics, but if it doesn't, then a fair amount of effort lies ahead. It may well take years to understand exactly how this new senolytic works to selectively provoke apoptosis in senescent cells. In this context, the discussion section of the paper is well worth a closer read; it gives a sense of the complexity of the challenge.

Identification of SYK inhibitor, R406 as a novel senolytic agent

Selective clearance of senescent cells has been suggested to induce rejuvenation and longevity. In animal models, senolytic drugs have been shown to delay several age-associated disorders, to improve physical and cognitive function, and to extend lifespan. Because known senolytic drugs have limited diversity for their mode-of-action and affect change in a cell-type-specific manner, novel senolytic drugs are needed to improve efficacy and expend medical application against senescent cells.

Major classes of senolytic drugs typically focus on inhibiting pro-survival pathways or triggering pro-apoptosis signaling in senescent cells. The combination of dasatinib and quercetin, which reduced p21, PAI-2, and BCL-xL, and Navitoclax (ABT263), which targets the Bcl-2 family, belong to this class of senolytics. In other classes, the mimicry of forkhead box protein O4 (FOXO4) peptide selectively disrupted the p53-FOXO4 interaction, which induced p53-dependent apoptosis in senescent cells. Recently, a HSP90 inhibitor was identified as a novel class of senolytic drugs that downregulated the phosphorylation of PI3K/AKT, an anti-apoptotic factor. Despite intensified efforts to develop drugs targeting senescent cells, however, the number of senolytic agents is still limited in comparison with the number of drugs against other age-related diseases like cancer or fibrosis.

In this study, using high-throughput screening to measure the variation of cell proliferation and reactive oxygen species (ROS) levels, we identified a novel senolytic agent R406, also known as tamatinib. This agent was effective in the replicative senescence model of diploid human dermal fibroblasts. R406 induced the caspase-9-mediated intrinsic apoptotic pathway, similar to other known senolytic drugs; however, R406 did not significantly change the level of Bcl-2 family in senescent cells. Alternatively, R406 inhibited the phosphorylation of focal adhesion kinase (FAK) as well as p38 mitogen-activated protein kinase (MAPK), which both regulate cell survival. Our results demonstrate that R406 is a new class of senolytics that targets multiple regulatory pathways for senescent cell survival.

Jim Mellon is doing a fair amount to help push the research and medical communities towards the development of therapies to slow and reverse the progression of aging. He is quite vocal in the business community, and is one of the founders of Juvenescence, very much involved in building portions of a longevity-focused biotechnology industry. He wrote a book on that topic as a part of convincing the broader investment community that this is an important new field. He has set up conferences, both for industry and for the broader community, such as the Longevity Forum. Here is an example of another approach, which is to fund institutional research programs to advance the state of the science.

We are delighted to announce that Jim Mellon (1975, PPE), British investor and philanthropist, has gifted £1 million to support and advance the study of Longevity Science at Oxford, and specifically at Oriel. The gift will establish the Mellon Longevity Science Programme at Oriel to help the most vulnerable in society by advancing research into health resilience in ageing populations. The gift is the largest of its kind dedicated to Longevity Science to a UK university, making Oriel and Oxford a focal point for efforts to improve future health resilience by boosting the immunity and healthspan of ageing populations. More specifically, the gift will support the work of Professor Lynne Cox, George Moody Fellow in Biochemistry at Oriel, and a principal investigator in the Department of Biochemistry. Her lab studies the molecular basis of human ageing, with the aim of reducing the morbidity and frailty associated with old age through better health resilience.

"There has never been a more important time to address the frailty of human health. The COVID-19 pandemic has highlighted the huge economic and social costs connected to the lack of immune resilience in our increasingly ageing population and the need for greater scientific research into this area. Boosting immunoresilience among the most vulnerable in society and advancing healthspan are critical to helping more people reach their potential as well as, more urgently, improving our collective resilience in the face of future pandemics. Oxford's leadership in the field of research and understanding of the ageing process makes it a natural home to advance longevity science and support the growth of the longevity industry, and I am proud to support this work."

Link: https://www.oriel.ox.ac.uk/about-college/news-events/news/orielensis-jim-mellon-gifts-%C2%A31-million-aid-research-improving-future

One of the more productive strategies undertaken by advocates and venture firms in the longevity industry is to put effort into the creation of companies, rather than waiting for companies to arise. This is still a small, young industry, without the sizable ecosystem that attends more mature areas of biotechnology, and thus many, many lines of research that might be productively developed into therapies targeting the mechanisms of aging remain stuck in academia. For investors and advocates to change this state of affairs requires building connections in the research community, introducing researchers and entrepreneurs, and helping research teams to make the transition into forming a company for commercial development. Investors are somewhat more efficient in conducting this sort of program, given that they have meaningful funding to hand, and so it is good to see more venture firms, such as Apollo Ventures, undertaking initiatives in company formation.

The idea that something might be done about age-related diseases using a repair-based approach targeting the root causes of aging was, for the most part, not taken seriously just a decade ago. What has happened in the last few years to increase acceptance and confidence in the idea?

I think the biggest change is the progress in aging science - over the last 10 years, scientific knowledge has evolved very quickly and reached a point where we finally understand what aging means on a molecular level and how we can fight it. Also, accelerating technologies like CRISPR and AI have catalyzed the entire longevity industry. At Apollo Ventures, we are leveraging this scientific progress to build the companies that will finally target the root cause of age-related diseases.

Can you tell us a little bit about the Moonshot Venture Fellowship?

The Moonshot Venture Fellowship is a 12-month program designed to give scientists the experience and support to create, launch, and build a venture-backed life science company based on outstanding science. For a scientist with a passion for translating research into medicines that make a difference for patients, the Moonshot Fellowship is an accelerated path to the skills to be a leader in life science companies. Our industry is a very young one. Thus, we believe that company building is needed to build up our industry. In the Moonshot Venture Program, either very senior pharma executives or biotech entrepreneurs are coming to us with an specific idea for a new company, or smart and ambitious postdocs who don't have a specific idea for a company but unique insights and expertise in a specific area of the longevity field.

Traditionally, there has been somewhat of a disconnect between basic research and spinning that off into a biotech company capable of developing and delivering a therapy to market. How exactly is the Moonshot Venture Fellowship helping to bridge that gap?

The postdocs that we hire do exactly that. Most of them are coming out of universities and have significant expertise in aging science when they join our program. They have about 6 months of time to speak with everybody in their field, visit conferences, and read papers. Together with us, they evaluate the best technologies and ideas they find during their research. Our team's expertise and long biotech experience is a great source to come up with a promising development plan. We help with tasks like IP evaluation, technology licensing, indication selection, and drug development plans. When all evaluations are positive, we found a company jointly with our fellows. Our support does not stop with the foundation of the company. We continue to be deeply engaged in the development of the company. Fundraising in our broad co-investor network and recruiting are two good examples where we can be really helpful for young companies.

Many promising startups fall foul of the "valley of death" before they can deliver to market and become profitable. How can programs such as the Moonshot Venture Fellowship help to mitigate this issue?

A program like ours can help to mitigate that issue, because apart from the scientific evaluation, we have the expertise, manpower and capital to commercialize such technologies. We are convinced that a clear clinical strategy and simply knowing who are the right co-investors for a project keep promising technologies from "drying out". Our team has co-invested with all the experienced biotech VCs. We actively fundraise for our companies in our network so that the team can focus on what they are good at, i.e. developing promising therapeutics for age-related diseases.

What do you see based on your experience as being the greatest bottleneck to getting rejuvenation biotechnology based approaches to aging from the bench to the bedside?

It is definitely, first and foremost, money. However, the situation is getting better quickly, as more and more VCs and institutional investors realize that the longevity field is developing real technologies, solving a very important problem and the biggest business opportunity out there.

Link: https://www.lifespan.io/news/the-moonshot-venture-fellowship/

Follistatin is an inhibitor of myostatin. Blocking myostatin activity enhances muscle growth, with accompanying beneficial side-effects such as a loss of excess fat tissue. This is well proven. There are a good number of animal lineages (mice, dogs, cows, and so forth) resulting from natural or engineered myostatin loss of function mutations, and even a few well-muscled human individuals with similar mutations. A number of groups are at various stages in the development of therapies to either upregulate follistatin or inhibit myostatin. The latter is further along in the formal regulatory process: human trials have been conducted for myostatin antibody therapies. Meanwhile, first generation follistatin gene therapies, such as that pioneered by BioViva Science, are available at great expense through the medical tourism market, such as via Integrated Health Systems, with all too little data on their efficacy.

In a world in which gene therapies become cheap and reliable, which will happen over the next ten to twenty years, follistatin upregulation will likely be one of the more widely available enhancement therapies. Who doesn't want more muscle, less fat, and a better metabolism, and all of that lasting for longer into later life? Unfortunately, gene therapy platforms are at present not all that efficient when it comes to systemic delivery throughout the body, at least not without a great deal of optimization to the specific use case. It is true that targeting muscle can be more a matter of scores of relatively unoptimized intramuscular injections rather than some form of infusion, but in both cases the cost is presently prohibitive for most people, and results in humans are yet to be robustly quantified. Expectations on safety are at present influenced more by the large numbers of mammalian myostatin loss of function mutants than by clinical data.

All of this said, it remains the case that work continues in laboratories to produce well muscled mice via follistatin gene therapies. The research noted here is an example of the type, a study that is little different from those performed in mice more than a decade ago. A few new assessments are made, and are interesting in and of themselves. Nonetheless, the wheels of science turn slowly indeed.

Gene therapy in mice builds muscle, reduces fat

Building muscle mass and strength can take many months and be difficult in the face of joint pain from osteoarthritis, particularly for older people who are overweight. A new study in mice, however, suggests gene therapy one day may help those patients. The research shows that gene therapy helped build significant muscle mass quickly and reduced the severity of osteoarthritis in the mice, even though they didn't exercise more. The therapy also staved off obesity, even when the mice ate an extremely high-fat diet.

The research team gave 8-week-old mice a single injection each of a virus carrying a gene called follistatin. The gene works to block the activity of a protein in muscle that keeps muscle growth in check. This enabled the mice to gain significant muscle mass without exercising more than usual. Even without additional exercise, and while continuing to eat a high-fat diet, the muscle mass of these "super mice" more than doubled, and their strength nearly doubled, too. The mice also had less cartilage damage related to osteoarthritis, lower numbers of inflammatory cells and proteins in their joints, fewer metabolic problems, and healthier hearts and blood vessels than littermates that did not receive the gene therapy. The mice also were significantly less sensitive to pain.

One worry was that some of the muscle growth prompted by the gene therapy might turn out to be harmful. The heart, for example, is a muscle, and a condition called cardiac hypertrophy, in which the heart's walls thicken, is not a good thing. But in these mice, heart function actually improved, as did cardiovascular health in general. Longer-term studies will be needed to determine the safety of this type of gene therapy. But, if safe, the strategy could be particularly beneficial for patients with conditions such as muscular dystrophy that make it difficult to build new muscle.

Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Follistatin (FST), a protein that binds myostatin and activin, may have the potential to enhance muscle formation while inhibiting inflammation. Here, we hypothesized that adeno-associated virus 9 (AAV9) delivery of FST enhances muscle formation and mitigates metabolic inflammation and knee OA caused by a high-fat diet in mice. AAV-mediated FST delivery exhibited decreased obesity-induced inflammatory adipokines and cytokines systemically and in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. Together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

This open access paper provides a good high-level overview of what is known of the molecular mechanisms underpinning the beneficial response to calorie restriction and intermittent fasting. In short-lived species, quite sizable gains in life span are possible, though this is not the case for longer-lived species such as our own. The metabolic responses to calorie restriction and intermittent fasting are not the same; they appear to function through an overlapping set of mechanisms, such that intermittent fasting without reduction in overall calories can still improve health and extend life.

The ultimate goal for animal studies on calorie restriction (CR) and intermittent fasting (IF) is to identify the conserved molecular mechanisms that can extend the healthspan of humans. Healthspan, the period of life that is free from disease, is measured by examining declines of functional health parameters and disease states. Because healthspan is a multifactorial complex phenotype that is significantly affected by genotypes (G) and environmental factors (E) as well as complicated interactions between them (G × E), measuring healthspan often gets complicated.

Delayed functional aging in one parameter is not always necessarily linked to the extension of healthspan in different health parameters. In fact, by depending on the types of health parameters and experimental approaches, different healthspan results were observed from the studies that used the same long-lived mutant animals. Unlike healthspan, lifespan is unequivocally recorded by simply following the mortality of individual organisms. Lifespan extension in animal models is strongly correlated with a decrease in morbidity and an increase in health. Therefore, although we believe that results of health-related parameters from animal CR/IF studies are likely to be translatable to human healthspan, we will focus on the mechanisms of lifespan extension.

Although not complete, studies for the last two decades on CR have provided a great amount of details about the mechanisms of CR. Recent advances in omics and bioinformatic techniques followed by organism level genetic perturbation analyses significantly extended our knowledge on the molecular mechanisms that mediate lifespan extension by CR. A current understanding is that CR works through the key nutrient and stress-responsive metabolic signaling pathways including IIS/FOXO, TOR, AMPK, Sirtuins, NRF2, and autophagy. While these pathways regulate CR independently, cross-talks among these pathways as well as upstream master networks such as circadian clock were also suggested to regulate lifespan extension by CR.

Although the number of reports on IF is less than CR, recent studies clearly demonstrated that IF also extends lifespan in both vertebrate and invertebrate model organisms. However, there is still a lack of comprehensive understanding for the mechanisms responsible for lifespan extension by IF. As nutrient-dependent interventions, CR and IF were suggested to share a common strategy: the reduction of caloric intake and nutrients that limit longevity. In fact, CR and IF also result in common metabolic and physiological changes in multiple tissues and organs. For example, ketone bodies, insulin sensitivity, and adiponectin are increased while insulin, IGF-1, and leptin are decreased. Overall inflammatory response and oxidative stress are reduced by both regimens. They also cause similar behavioral changes such as increased hunger response and cognitive response.

Accordingly, it is widely accepted that common molecular mechanisms may mediate the lifespan extension by CR and IF. A proposed model for the mechanisms underlying the lifespan extension by CR and IF relatively follow the notion that both CR and IF alter the activity of common key metabolic pathways, namely, TOR, IIS, and sirtuin pathways. However, there must be independent mechanisms as well due to one major difference between CR and IF in that IF aims to extend lifespan without an overall reduction in caloric intake by taking advantage of the molecular pathways that respond to fasting.

Link: https://doi.org/10.3390/nu12041194

Researchers here show that the gene Lin28 regulates axon regrowth. In mice, raised levels of Lin28 produce greater regeneration of nerve injuries. Past research has investigated Lin28 from the standpoint of producing a more general improvement in regenerative capacity. It improves mitochondrial function, thus providing additional energy for cellular growth and replication. Researchers here employ a viral vector to deliver Lin28 to mice, which is a first step on the long road towards clinical applications. Practical therapies remain years in the future, however.

"Our findings show that Lin28 is a major regulator of axon regeneration and a promising therapeutic target for central nervous system injuries. We became interested in Lin28 as a target for neuron regeneration because it acts as a gatekeeper of stem cell activity. It controls the switch that maintains stem cells or allows them to differentiate and potentially contribute to activities such as axon regeneration."

To explore the effects of Lin28 on axon regrowth, researchers developed a mouse model in which animals expressed extra Lin28 in some of their tissues. When full-grown, the animals were divided into groups that sustained spinal cord injury or injury to the optic nerve tracts that connect to the retina in the eye. Another set of adult mice, with normal Lin28 expression and similar injuries, were given injections of a viral vector for Lin28 to examine the molecule's direct effects on tissue repair.

Extra Lin28 stimulated long-distance axon regeneration in all instances, though the most dramatic effects were observed following post-injury injection of Lin28. In mice with spinal cord injury, Lin28 injection resulted in the growth of axons to more than three millimeters beyond the area of axon damage, while in animals with optic nerve injury, axons regrew the entire length of the optic nerve tract. Evaluation of walking and sensory abilities after Lin28 treatment revealed significant improvements in coordination and sensation.

Link: https://www.templehealth.org/about/news/temple-scientists-regenerate-neurons-in-mice-spinal-cord-injury-optic-nerve-damage

Nutraceuticals are compounds derived from foods, usually plants. In principle one can find useful therapies in the natural world, taking the approach of identifying interesting molecules and refining them to a greater potency than naturally occurs in order to produce a usefully large therapeutic effect. Unfortunately, in practice the nutraceutical industry is a largely a lazy one, in which entrepreneurs take advantage of a short path to market, and a lack of interest among consumers in whether or not products actually work, in order to repackage cheap ingredients into expensive brands that have minimal, unreliable, or even no beneficial effects.

In today's open access paper, researchers discuss the potential for nutraceutical research and development to produce useful senolytic compounds. A senolytic therapy is one that selectively kills senescent cells in aged tissues, thus reversing aspects of aging by removing the inflammatory, harmful signaling of these cells. This class of therapy has performed well in animal models, and early human trials continue to produce promising outcomes.

Any survey of nutraceutical development is, as noted above, going to include a lot of useless, overhyped lines of work. Just because a mechanism exists doesn't mean that the mechanism produces a large enough benefit to be therapeutic, and tiny to nonexistent effect sizes are characteristic of nutraceutical development. It is safe to tune out any time compounds in green tea are mentioned, for example. Still, some plant extract senolytics, such as fisetin and piperlongumine, do appear to have interestingly large effects in animal studies - even similarly sized to the small molecule chemotherapeutic senolytics. Whether they do as well in human trials remains to be seen, but making the attempt is not unreasonable based on the animal data.

An Appraisal on the Value of Using Nutraceutical Based Senolytics and Senostatics in Aging

Recent studies argue for a pathogenic role of senescent cells, which contribute to a range of aging related diseases, such as osteoarthritis, cardiovascular disease, and cataract. Senescent cells are found in aging related cognitive decline but also in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Therefore, the possible application of senolytics in a wide range of clinical scenarios is becoming an attractive concept. Senolytics could be used as a preventative in the elderly, as a supplement to clear senescent cells to thus improve or maintain tissue and organ health. They are also being looked at as an adjuvant cancer therapy, with the aim of clearing treatment-induced senescent cells and thus reducing the probability of relapse.

Synthetic compounds with senolytic or senostatic properties can be effective, however, they are not specific, and systemic side effects can be severe and deleterious to healthy cells. Hence, a movement toward the research of natural based compounds (nutraceuticals) with potential anti-senescence properties has begun. Nutraceuticals are bioactive compounds derived from food, including plant material, with physiological benefits in the prevention or treatment of disease. For instance, polyphenols, found in high abundance in plants, are bio-active compounds with anti-oxidant and anti-inflammatory properties making them potential senostatics by negating the pro-oxidant and pro-inflammatory signaling of senescent cells. The aim remains to find potential anti-aging therapies that are effective but exhibit minimal side effects, and some natural plant-based compounds could fit this criterion.

In vitro, two olive phenols called hydroxytyrosol (HT) and oleuropein aglycone (OLE) have shown to counteract senescence via significant reductions in SA-β-Gal staining, p16 levels, and senescence-associated secretory phenotype (SASP) levels in human lung fibroblasts and neonatal human dermal fibroblasts. Catechin is a tannin found in green tea that exists in multiple forms, including Epigallocatechin gallate (EGCG). Research investigating the effects of EGCG against replicative senescence in cells has shown the potential senostatics effects of the nutraceutical. Fisetin is bioactive flavonol molecule. Naturally aged C57BL/6 mice treated orally at 22-24 months with 100 mg/kg fisetin for 5 days showed a reduction in senescent cells in white adipose tissue. Additionally, fisetin treatment at 85 weeks of age significantly prolonged life-span of these mice by an additional 3 months. Resveratrol treatment in endothelial progenitor cells (EPCs) also showed prevention of replicative senescence. However, when a large-scale in vivo study of resveratrol in genetically heterogenous (outbred) mice was conducted in parallel with rapamycin treatment, analysis of activity showed that there was no significant difference between control and resveratrol-treated mice.

For senolytics to be widely used in aged but otherwise healthy populations to prevent tissue dysfunction, unwanted side effects have to be kept to the minimum. The use of nutraceutical based senolytics could result in fewer complications, while retaining anti-senescent effects. Despite promising in vitro reports, the data on the in vivo efficacy of nutraceutical senolytics is still sparse and, in some cases, contradictory. Thus, more research is still needed to determine whether they could be an attractive alternative to the most used chemical senolytics, such as dasatinib + quercetin, which have shown promising results in preliminary short-term clinical trials.

A number of receptor tyrosine kinases are implicated in areas of metabolism known to influence the pace of aging in short-lived laboratory species. Researchers here investigate Alk, a receptor tyrosine kinase previously understudied in this context. It isn't clear that this will do any better as a basis for human therapies. In general this class of efforts to manipulate metabolism produces diminishing returns as species life span increases. Short-lived worms, flies, and mice exhibit a life span that can vary widely in response to environmental circumstances and changes in metabolism. We long-lived humans do not.

Inhibition of signalling through several receptor tyrosine kinases (RTKs), including the insulin-like growth factor receptor and its orthologues, extends healthy lifespan in organisms from diverse evolutionary taxa. This raises the possibility that other RTKs, including those already well studied for their roles in cancer and developmental biology, could be promising targets for extending healthy lifespan. Here, we focus on anaplastic lymphoma kinase (Alk), an RTK with established roles in nervous system development and in multiple cancers, but whose effects on aging remain unclear.

We find that several means of reducing Alk signalling, including mutation of its ligand jelly belly (jeb), RNAi knock-down of Alk, or expression of dominant-negative Alk in adult neurons, can extend healthy lifespan in female, but not male, Drosophila. Moreover, reduced Alk signalling preserves neuromuscular function with age, promotes resistance to starvation and xenobiotic stress, and improves night sleep consolidation. We find further that inhibition of Alk signalling in adult neurons modulates the expression of several insulin-like peptides, providing a potential mechanistic link between neuronal Alk signalling and organism-wide insulin-like signalling. Finally, we show that TAE-684, a small molecule inhibitor of Alk, can extend healthy lifespan in Drosophila, suggesting that the repurposing of Alk inhibitors may be a promising direction for strategies to promote healthy aging.

Link: https://doi.org/10.1111/acel.13137

Epigenetic markers on DNA determine the pace and timing of protein production, and are thus one of the important influences on cell and tissue function. Cells adjust their epigenetic programs in response to the surrounding environment, but alterations can be lasting. It is thought that environmental influences on epigenetic programming of cellular behavior that occur in childhood set the stage for faster or slower onset of metabolic dysfunction in later life, once cell and tissue damage starts to accumulate. Researchers here provide a proof of principle of this process in rats.

Environmental exposures during early life exert a profound influence on developing organs, which can affect health across the life-course, and even transgenerationally. The adverse health impact of these exposures is thought to be mediated by reprogramming of normal physiologic responses, and forms the basis of the developmental origins of health and disease (DOHaD) paradigm. Fetal over- or under-nutrition has been linked to metabolic dysfunction in adulthood and increased risk for metabolic diseases including obesity, diabetes, and metabolic syndrome. Besides nutritional stressors, early-life exposures to environmental chemicals, including endocrine-disrupting chemicals (EDCs), can influence health and disease susceptibility across the life-course.

EDCs are defined as exogenous chemicals, or mixture of chemicals, that interfere with hormone action and many have been shown to impact metabolic function, and increase disease risk in metabolic organs such as the liver. Recently, the epigenetic machinery has emerged as a target for EDCs and other environmental exposures. When this machinery is perturbed early in life, the resulting epigenetic alterations can persist long after the initial environmental insult (often referred to as developmental reprogramming). Accordingly, research on the causes of the epidemic rise in metabolic diseases has expanded beyond genetics, over-nutrition, and energy expenditure to include the role of early-life EDC exposures. However, little is known about what determines vulnerability to early-life exposures, or specific targets and pathways linking developmental reprogramming by early-life exposures to later-life metabolic dysfunction.

Using a rat model for exposure to an endocrine disrupting chemical (EDC), we show that early-life chemical exposure causes metabolic dysfunction in adulthood and reprograms histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature. This epigenomic reprogramming persists long after the initial exposure, but many reprogrammed genes remain transcriptionally silent with their impact on metabolism not revealed until a later life exposure to a Western-style diet. Diet-dependent metabolic disruption was largely driven by reprogramming of the Early Growth Response 1 (EGR1) transcriptome and production of metabolites in pathways linked to cholesterol, lipid, and one-carbon metabolism.

Link: https://doi.org/10.1038/s41467-020-15847-z

Today's open access paper is interesting on two counts. Firstly as one of a number of studies in recent years examining the effects of age-related changes in the gut microbiome via fecal transplantation between young and old animals. Secondly, it suggests that negative effects on cognitive function resulting from these changes is mediated by chronic inflammation generated by the interaction of harmful gut microbes with the immune system.

There is a growing interest in the age-related shift in microbial populations in the gut. Researchers have identified some important metabolites that are generated at lower levels in older people as a result of loss of beneficial microbes. These include butyrate, propionate, and indole. Supplementation is a possibility, but this is by no means a comprehensive list, and that will not solve all of the other issues, such as growing populations of harmful microbes aggravating the immune system to generate chronic inflammation. Fixing the balance of populations is the more sensible path forward, and given sufficient funding for development and trials, the medical community might deploy fecal microbial transplantation from young to old as an intervention.

It is quite unclear as to why microbial populations change for the worse with age. The direction of causation between immune dysfunction and a worse gut microbiome might be in either direction. The earliest significant changes occur around age 35, which seems far too young for any of the obvious mechanisms of aging to be producing meaningful pathology. There are many potential contributing causes in later life, including the aforementioned immune dysfunction, dietary changes, lack of exercise, and declining tissue function of the intestines. Establishing which of these causes are actually important is very much a work in progress.

Age-related shifts in gut microbiota contribute to cognitive decline in aged rats

The human gastrointestinal tract harbors a complex and dynamic population of microorganisms, referred to as gut microbiota. The gut microbiota is very important for the development and homeostasis of the body; it regulates intestinal motility and gastrointestinal barrier, host energy metabolism and mitochondrial function, as well as immune responses and the central nervous system. In adulthood, the microbiota reaches a relative equilibrium, and does not significantly change under stable environmental and health conditions. Generally, the phyla Bacteroidetes and Firmicutes dominate the intestine for adulthood. However, with an increasing age, the gut microbiota undergoes a profound remodeling. Researchers have shown that the gut microbiota of the elderly is substantially different from the younger adults, and correlates with frailty. However, given our current inability to delineate the most significant effector mechanisms involved in the host-microbiota interactions over a lifetime, it is difficult to tease apart causality from correlation.

Although some animal studies indicated that the gut microbiota affects learning and memory, these reports were based on special animal models, such as germ-free (GF) mice, or on various artificial interventions that change the gut microbiota, such as pathogenic bacterial infection, probiotics, and antibiotics. Since the aging process and aging biological characteristics were not considered in these studies, they were not able to uncover the association between gut microbiota and cognitive function under normal aging process. Given these findings, we hypothesized that alterations in the gut microbiota contribute to cognitive decline in aging. In this study, we transplanted the gut microbiota from aged rats to young rats by using the fecal microbiota transplantation (FMT) technique, to observe whether the reshaped gut microbiota can cause a shift in cognitive behavior, brain structure, and functions in the young recipient rats. To our knowledge, this is the first study that investigates the effect of gut microbiota on cognitive decline in normal aging process.

Results showed that FMT impaired cognitive behavior in young recipient rats; decreased the regional homogeneity in medial prefrontal cortex and hippocampus; changed synaptic structures and decreased dendritic spines; reduced expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor NR1 subunit, and synaptophysin; increased expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE). All these behavioral, brain structural and functional alterations induced by FMT reflected cognitive decline. In addition, FMT increased levels of pro-inflammatory cytokines and oxidative stress in young rats, indicating that inflammation and oxidative stress may underlie gut-related cognitive decline in aging. This study provides direct evidence for the contribution of gut microbiota to the cognitive decline during normal aging and suggests that restoring microbiota homeostasis in the elderly may improve cognitive function.

Mitochondria, the power plants of the cell, decline in function with age. This contributes to the development of age-related conditions, particularly in energy-hungry tissues such as muscle and brain. An important proximate cause of this failure is disruption of mitophagy, a form of the cellular maintenance process of autophagy that recycles damaged mitochondria. This in turn might be due to an imbalance of fission and fusion of mitochondria, leading to large mitochondria that are resistant to mitophagy. It may also be due to various dysfunctions in mechanisms of autophagy that emerge in old tissues. The underlying causes below that level are poorly understood, but interventions that enhance autophagy are one possible starting point for the development of therapies to improve faltering mitochondrial function in older people.

A decline in mitochondrial function is a hallmark of the aging process and is connected to other aging hallmarks such as telomere dysfunction, genome instability, and cellular senescence. However, it remains largely unclear how these processes are interconnected and finally provoke disruption of the cellular and tissue integrity. There is accumulating evidence that mitophagy impacts health- and lifespan in different model organisms. The effect of changes in mitophagy on health- and lifespan has been particularly demonstrated by using the model organisms C. elegans and D. melanogaster. Several genetic studies in D. melanogaster revealed that the overexpression of mitochondrial and mitophagy genes leads to increased health- and/or lifespan. For instance, the overexpression of the mitochondrial fission protein dynamin-related protein 1 (DRP1) increased the lifespan along with a prolonged healthspan in flies.

An increasing number of human diseases have been associated with impaired mitophagy, thus, interventions that modulate mitophagy may provide the possibility of counteracting disease development or progression. In recent years, multiple small molecules as well as lifestyle interventions have been shown to modulate autophagy, thereby causing health- and lifespan benefits in different organisms. Due to the dependency on core autophagy regulators, mitophagy is modulated by most of the classic autophagy inducers such as the mTOR inhibitor rapamycin, the AMP-activated protein kinase (AMPK) activator AICAR, as well as caloric restriction and exercise.

Mitophagy is emerging as a central process preserving organismal and, especially, neurological health. Since most trials targeting age-associated neurodegeneration in the last decades have been disappointing, new pharmaceutical avenues are direly needed. Here, mitophagy stimulators could play a key role. Indeed, several clinical trials are underway testing the efficacy of mitophagy modulating compounds and the outcome of these studies will undoubtedly prove critical for the future translatability of the field. Nonetheless, the regulatory mechanism of mitophagy and its contribution to age-associated diseases still remains elusive and potential issues with artificially augmenting mitophagy have not been considered. However, given the central role of mitophaging in multiple age-related pathologies it appears highly likely that these new promising approaches may present possible interventions in age-associated diseases. The future is bright!

Link: https://doi.org/10.3389/fcell.2020.00239

Mitochondrial DNA damage is a contributing cause of aging, and researchers here look at this issue in the context of the aging of heart tissue. Mitochondria are the power plants of the cell, a herd of bacteria-like structures that contain their own small genome, and work to produce the chemical energy store molecule adenosine triphosphate. This is an energetic process that produces oxidative molecules as a byproduct, capable of damaging cellular machinery and requiring maintenance and antioxidant processes as a defense. Mitochondria are destroyed by the quality control mechanism of mitophagy when damaged, and replicate to make up their numbers.

Some forms of mitochondrial DNA damage can subvert quality control and lead to problem cells overtaken by broken mitochondria, exporting harmful reactive molecules into the surrounding tissue. Ways to repair or replace damaged mitochondrial DNA will likely turn back aspects of aging by removing a source of damage and dysfunction, but the various approaches to this challenge are as yet still comparatively early in the development process.

Cardiac aging resulting in defects in cardiac mitochondrial function centers on the mitochondrial DNA (mtDNA) damage. The mechanisms of the alterations in the aging heart mainly involve mitochondrial dysfunction, altered autophagy, chronic inflammation, increased mitochondrial oxidative stress, and increased mtDNA instability.

Reactive oxygen species (ROS) play a pivotal role in healthy cellular and mitochondrial signaling and functionality. However, if unchecked, ROS can mediate oxidative damage to tissues and cells, leading to a vicious cycle of inflammation and more oxidative stress. Meanwhile, mitochondria, the major source of ROS, are thought to be particularly vulnerable to oxidative damage. Because of its richness in mitochondria and high oxygen demand, the heart is at high risk of oxidative damage. The most supportive evidence of the central role of mitochondrial ROS in the aged heart is that overexpression of catalase targeted to mitochondria attenuates cardiac aging.

A growing body of evidence suggests that there is increasing oxidative damage to mitochondrial DNA in cardiac aging. Because of the histone deficiency, limited DNA repair capabilities, and proximity of mtDNA to the site of mitochondrial ROS generation, mtDNA can suffer various types of damage, including mtDNA point mutations, mtDNA point deletions, and decreased mtDNA copy number (mtDNA-CN). The continuous replicative state of mtDNA and existence of the nucleoid structure render mitochondria vulnerable to oxidative damage and mutations.

DNA polymerase gamma (DNA Pol γ) plays a vital role in mtDNA replication. DNA Pol γ has two main functions: mtDNA synthesis and proofreading. Recent studies report that ROS reduces the proofreading ability of Pol γ, causing replication errors. Thus, oxidation aggravating mtDNA mutations causes replication errors, which indirectly cause mtDNA damage. This proves that mtDNA mutations are largely random, and Pol γ oxidation is likely to account for mtDNA mutations in aging. Therefore, mtDNA mutation may be highly associated with heart aging, and the repair of damaged mtDNA provides a potential clinical target for preventing cardiac aging.

Link: https://doi.org/10.1155/2020/9423593

Today I'll note the development of a commercial aging clock based on glycosylation patterns of immunoglobulin G, a marker for the inflammatory status of the immune system, by startup biotech company GlycanAge. There are at present any number of approaches to measuring biological age, the burden of cell and tissue damage that leads to dysfunction. Stage of development varies widely, with the most work to date being on clocks based on changes in DNA methylation. There are also clocks that use protein levels in blood, weighted combinations of simple measures such as grip strength, and other approaches besides these. The important goal in these efforts is to produce a measure that can quickly be applied before and after a potential intervention to quantify the degree to which it reverses aging. A generally accepted, fast, cheap measure of age would greatly accelerate development of rejuvenation therapies, and might finally focus more research attention on repair-based interventions that have a greater chance of producing large effect sizes.

That still lies a way in the future, however. The challenge with near all of these clocks is that they are constructed by comparing data that is far downstream of the causes of aging against outcomes such as mortality risk. Thus there is no good understanding of what exactly it is that these biomarkers of aging are actually measuring, under the hood. The glycosylation clock is more clear than most, in that it is very directly an assessment of the chronic inflammation of aging, but even then it is a challenge to say which underlying causes of aging are more or less important in that outcome. The situation is much murkier for other clocks.

This lack of knowledge means that a clock must be calibrated against each potential intervention, in the slow, hard way, by waiting to assess lifespan, in order to ensure that it is a valid test. This somewhat defeats the point of the exercise, to make development faster for new interventions. Further, it means that most of the commercially available tests are not actionable: the test will produce a number, but that number says nothing about what might be done to change it. The glycosylation clock is at least ahead of the game on that front, pointing directly to whatever approaches are known to reduce chronic inflammation, but this may or may not still be somewhat disconnected from other processes of aging.

Start-up claims first commercial glycan-based age test

GlycanAge is a British-Croatian start-up focused on analysing glycosylation patterns to deliver what it claims is the "most accurate" measure of biological age. Glycans are complex sugars that contribute significantly to the structure and function of the majority of proteins. Changes in glycans have been reported in many inflammatory diseases, where they reflect disease activity, or in some cases even precede the development of disease.

The company, leveraging patents from leading glycomics research lab Genos, has developed a direct-to-consumer glycan test kit that measures biological age and chronic low grade systemic inflammation. When the company first started in 2016, it worked using plasma samples, which was expensive and hard to scale commercially, but it has since developed a dry blood spot based test that delivers the same results.

"Telomeres are DNA timers that limit the lifespan of a single cell. On the individual cell level, telomeres are the best marker of aging. However, we are composed of trillions of cells and each of them has different age and expected lifespan. GlycanAge is different because it measures your immunoglobulin G glycosylation, which directly correlates with the level of inflammation in your body. It will give you information about the immune balance of your organism that changes with age, health and life circumstances."

GlycanAge

GlycanAge is a science-based test that will accurately determine your biological age. This is a first commercial glycan-based test that will put a single number to your health. Glycans are complex sugar molecules (carbohydrates), and one of the four main building blocks of life. They are involved in almost every process in our body.

More than half of all our proteins are glycosylated, with their glycan parts often playing an essential functional role. Glycans are crucial for the functioning of our immune system. Glycans attached to the antibodies modulate their activity and determine if they will have a pro-inflammatory or anti-inflammatory function. Thus, it is not surprising that glycan profiles can serve as a measure of an individual's health. The GlycanAge test looks at the glycosylation pattern of the immunoglobulin G (IgG) molecule. IgG is the most prevalent antibody type in our blood and especially important in controlling inflammation and pathogens.

Immunoglobulin G (IgG), the most prevalent antibody type in our blood, is always glycosylated - meaning it has glycans attached to it. The type of the glycan group attached to the IgG determines if IgG will enhance or reduce inflammation. Since inflammation can exhaust our resources to keep the body in good health, low level of inflammation was shown to be a predictor of successful ageing. Therefore, IgG glycosylation is also a good measure of biological age.

When looking at any of the work presently taking place on improving metabolism in older individuals, whether by stress response upregulation, or by improving mitochondrial function, it is always worth checking the human data, where it exists, to compare the effect size with that of exercise. This open paper is a useful resource when comparing exercise to the class of approaches that fairly directly increase levels of NAD+/NADH. These molecules are involved in mitochondrial function, and for various reasons - decline in recycling, decline in synthesis - become less available with age.

A number of supplements and treatments are on the market or under development to increase NAD+ levels in older people, and an initial human trial has been published for nicotinamide riboside. In that trial, nicotinamide riboside supplementation boosted NAD+ by 60% or so in immune cells from a blood sample. In the paper here, NAD+ was more than doubled in muscle cells following ten weeks of resistance training, restoring levels in older people to that of collage-aged individuals. This is not an apples to apples comparison, but worth considering while thinking about the present enthusiasm for NAD+ upregulation. The long term effects of exercise and resistance training are quite well catalogued, and while beneficial, do not greatly extend life.

Nicotinamide adenine dinucleotide (NAD+) is a metabolite involved in numerous biochemical reactions. In particular, NAD+ is involved with electron transport where the reduced form (NADH) transfers electrons to other substrates and intermediates of metabolism. There is enthusiasm surrounding the role that tissue NAD+ concentrations play in the aging process, and researchers have determined skeletal muscle NAD+ concentrations are lower in older rodents and humans. These findings have led some to suggest that the age-associated loss in skeletal muscle NAD+ levels contributes to mitochondrial dysfunction. NAD+ biosynthesis can be catalyzed through the salvage/recycling pathway, and nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in this pathway. Beyond its involvement with redox reactions, NAD+ binds to and activates a class of enzymes that possess deacetylase activity called sirtuins (SIRTs).

Endurance training appears to be capable of increasing skeletal muscle markers related to NAD+ and SIRT signaling. For instance, endurance training in rodents and humans has been shown to modulate SIRT1 and SIRT3 protein levels and increase the activity of these enzymes in skeletal muscle. Additionally, skeletal muscle NAMPT protein levels have been reported to be higher in endurance-trained athletes versus untrained individuals. However, there is a paucity of research examining these biomarkers in response to resistance training. It remains plausible that resistance training can increase skeletal muscle markers related to NAD+ biosynthesis and SIRT signaling, and this may be an involved mechanism in facilitating training adaptations.

Given the paucity of data in this area, we sought to examine the effects of resistance training on skeletal muscle NAD+ concentrations as well as NAMPT protein levels, SIRT1/3 protein levels, and markers of SIRT activity in middle-aged, overweight, untrained individuals. In the middle-aged participants, the 10-week training intervention: i) promoted training adaptations (i.e., increased strength and localized hypertrophy), ii) robustly increased muscle NAD+ and NADH concentrations, iii) modestly (but significantly) increased NAMPT protein levels and global SIRT activity, and iv) robustly increased citrate synthase activity levels in muscle suggesting mitochondrial biogenesis occurred. This is the first evidence to suggest resistance training in middle-aged individuals restores muscle NAD+ and NADH concentrations to levels observed in recreationally-trained college-aged individuals.

Link: https://doi.org/10.18632/aging.103218

The wet form of age-related macular degeneration involves an excessive growth of blood vessels behind the retina, disrupting structure to produce a progressive and presently irreversible loss of vision. Researchers here point out a role for IL-4 in this process, though the mechanisms involved are probably a fair way downstream from the causes of chronic inflammation and immune system dysfunction that spur the development of macular degeneration. Sometimes it is a possible to find a good place to sabotage the development of pathology that is distant from the root causes, but the odds are not favorable. More commonly, later stage intervention is the path to only marginally effective therapies.

Scientists have identified an unexpected player in the immune reaction gone awry that causes vision loss in patients with age-related macular degeneration (AMD). The findings suggest that an immune-stimulating protein called interleukin-4 (IL-4) and its receptor may be promising targets for new drugs to treat AMD, a common form of age-related vision loss. In patients with AMD, inflammation in the eye triggers excessive growth of new blood vessels in the center of the retina. This process damages the photoreceptors in the eye and leads to progressive vision loss.

The team measured levels of IL-4 in the eyes of 234 patients with AMD and 104 older individuals undergoing surgery for cataracts. They found that those with AMD had higher levels of IL-4 than those undergoing surgery. Next, they found that IL-4 was also elevated in mice with a condition that mimics AMD. To determine if IL-4 was helping or harming the animals, they administered them with IL-4 and found that it increased the excessive growth of blood vessels in the eye. An antibody that blocks IL-4 production reduced this blood-vessel growth. Mice with the AMD-like condition that were genetically engineered to lack IL-4 also had less blood-vessel growth.

"Our results show that IL-4 plays a crucial role in excessive blood-vessel growth by recruiting bone marrow cells that aid this growth to the lesion in the eye. These results were surprising and suggest that normally helpful immune responses can instead cause more harm,. As IL-4 plays a key disease-promoting role in AMD, it may serve as a target for new treatments to treat this condition." Normally, bone marrow cells help the body repair damaged tissues, while IL-4 helps suppress excessive blood vessel growth.

Link: https://elifesciences.org/for-the-press/75a384d0/study-finds-unexpected-suspect-in-age-related-macular-degeneration

The gerontology community is most interested in identifying and quantifying the mechanisms that determine species longevity. Why do different mammalian species have radically different life spans, from the year of a shrew to the centuries of large whales? Some inroads have been made into which portions of cellular metabolism are likely contributing to sizable life span differences, but there is no map of relative contributions or exhaustive list of mechanisms - this is a project that still has a long way to go before completion.

Will knowing more about species life span determination help in producing interventions to increase longevity in our species? This may or may not be the case. There is no particular reason why the important factors in species life span must correlate well with the classes of therapy that will produce rejuvenation. A given species will accumulation forms of molecular damage and dysfunction at a given pace, and effective periodic repair of that damage may well involve completely different mechanisms to those that determine the rate at which damage accumulates.

One area of overlap between mechanisms known to be of interest to species longevity and mechanisms known to be of interest to aging within a species is the structure and function of mitochondria. Mitochondrial dysfunction is prevalent in aging, for reasons that appear to involve an imbalance of fusion and fission of mitochondria, and a consequent failure of the quality control mechanism of mitophagy. Equally, mitochondrial DNA damage can produce mutant mitochondria that overtake cells and cause them to export damaging reactive molecules into surrounding tissue. In the study of aging and life span by species, researchers have shown that mitochondrial composition and metabolic rate correlate well with species life span, giving rise the the membrane pacemaker theory of aging. Some species have mitochondria that are more resilient to oxidative damage, which can slow the onset of dysfunction with aging.

Today's open access paper is an interesting addition to this body of literature. Researchers show that some components of mitochondrial machinery vary in abundance in ways that correlate with mammalian species life span. This seems likely to affect the generation of oxidative molecules by mitochondria, and thus also alter the balance of oxidative damage and mitochondrial dysfunction. This part of the field is still very much a collection of correlations and hypotheses, however. It is quite possible to argue for other interpretations of what is observed, or to expect that more data might upturn an existing consensus.

Low abundance of NDUFV2 and NDUFS4 subunits of the hydrophilic complex I domain and VDAC1 predicts mammalian longevity

Complex I (Cx I) (NADH-ubiquinone oxidoreductase) is an electron entry point in the mitochondrial respiratory electron transport chain (ETC). Cx I catalyses NADH oxidation reducing ubiquinone to ubiquinol, importantly contributing to the proton motive force used to synthesize ATP by the oxidative phosphorylation. Cx I also produce reactive oxygen species (ROS), initially superoxide radicals, which can damage all cellular components. Although at least 11 sites producing ROS have been identified, Cx I and complex III (Cx III) are conventionally recognized as the major sources of ROS at the ETC. Mitochondrial ROS production (mitROSp) has been considered one of the main effectors responsible for aging and longevity.

Low rates of mitROSp have been described in many long-lived mammalian and bird species. These studies generally demonstrated the existence of a negative correlation between mitROSp and longevity. Among the two main ROS generating ETC complexes, the low ROS production of various long-lived species has been localized at Cx I. Interestingly, different pro-longevity nutritional and pharmacological interventions like dietary restriction (DR) and methionine restriction, and rapamycin treatment have been also associated with decreased mitROSp at Cx I.

Mammalian Cx I is the largest component of the ETC built of 45 different subunits in mammals. Among the 14 core subunits, the 7 mitochondrial-encoded ND subunits are present in the hydrophobic membrane domain, and the other 7 nuclear-encoded (NDUF) subunits are present in the hydrophilic matrix domain. The 31 supernumerary NDUF accessory subunits are also nuclear coded. However, it is totally unknown if some particular Cx I subunits, especially some NDUF subunits of the Cx I hydrophilic domain, could be involved in the determination of the longevity-related low complex I ROS production of long-lived animal species.

The present study follows a comparative approach to analyse Cx I in heart tissue from 8 mammalian species with a longevity ranging from 3.5 to 46 years. Gene expression and protein content of selected Cx I subunits were analysed. Our results demonstrate: 1) the existence of species-specific differences in gene expression and protein content of Cx I in relation to longevity; 2) the achievement of a longevity phenotype is associated with low protein abundance of subunits NDUFV2 and NDUFS4 from the matrix hydrophilic domain of Cx I; and 3) long-lived mammals show also lower levels of VDAC (voltage-dependent anion channel) amount. These differences could be associated with the lower mitochondrial ROS production and slower aging rate of long-lived animals and, unexpectedly, with a low content of the mitochondrial permeability transition pore in these species.

This study is interesting on a few counts. Firstly, transfusion of old individuals with plasma from young individuals has failed to produce usefully large benefits in human trials, and the evidence in mice looks similarly shaky. Yet here, in rats, benefits are observed with a specific approach to producing a plasma fraction for use in therapy. The authors do not divulge details regarding the methodology of production, as they intend commercial development in the near future. Secondly, it connects epigenetic age reduction with reduction in senescent cell burden. It is worth noting that the epigenetic clocks used here to assess biological age are new, not existing clocks, however. The reduction in senescent cells is thus the more interesting measure to result from the study. As a final note, only a small number of rats were used in the plasma transfusion portion of the study, so this is very much a result that requires replication.

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data.

We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

Link: https://doi.org/10.1101/2020.05.07.082917

We live in a world in which most people do not undertake anywhere near the level of physical activity that is optimal. Thus adding greater physical activity as a lifestyle choice appears very beneficial. There is a great deficiency, one that has serious consequences to health, and fixing that deficiency is touted as a successful intervention. But in reality, the situation is one in which most people harm their long term health through a form of self-neglect. This era of cheap calories and comfort is a time of vast benefits for humanity - but it has a few downsides, and this is one of them.

This meta-analysis showed a protective effect of physical activity to successful aging among the middle-aged and older adults. The protective effect of physical activity to successful aging was larger on the younger group than the older group. Being physically active in earlier life is beneficial to successful aging in later life. However, the effect of physical activity on successful aging decreased as time elapsed. Physically active middle-aged and older adults were more likely to age successfully than sedentary adults (odds ratio 1.64). The effect of physical activity was stronger in the younger group (odds ratio 1.71) than on the older group (odds ratio 1.54). The protective effect of physical activity reduced annually by approximately 3%.

Physical activity prevents the development of many chronic diseases, including metabolic syndrome, type 2 diabetes, coronary artery disease, hypertension, stroke, dyslipidemia, cognitive impairment, depression, osteoarthritis, osteoporosis, colon cancer, breast cancer, non-alcoholic fatty liver disease, and sarcopenia. Physical activity also increases longevity and survival. For middle-aged and older people, a dose-response relationship was found between physical activity and decrease in mortality. Compared with sedentary older people, physically active older adults were more likely to remain living independently. Physical activity in old age preserves the cognitive and physical functions. These previous findings supported the main finding of the present meta-analysis.

Physical activity is a protective factor of successful aging in the middle-aged and older adults. Although some included studies showed a weak association between physical activity and successful aging, most studies reported a consistent positive relationship. Further research is warranted to establish the dose-response relationship between physical activity and successful aging as well as to reduce the effects of time.

Link: https://doi.org/10.18632/aging.103057

Chemotherapy and radiotherapy remain the presently dominant forms of cancer treatment. Immunotherapies are making slow inroads, but remain a minority of all treatments. Both chemotherapy and radiotherapy kill cells and force cells into senescence, cancerous cells and otherwise. They are a balance struck between killing the cancer and killing healthy tissue, and are are not pleasant at all for the patient. Cancer survivors have a significantly reduced life expectancy, as large as that resulting from life-long smoking, and evidence strongly suggests that this is due to a significantly increased burden of >senescent cells left behind following treatment.

Cells become senescent for many reasons, including the DNA damage and environmental toxicity produced by chemotherapies and radiotherapies. Senescence is a state of growth arrest in which cells bloat, cease to replicate, and begin to secrete an inflammatory mix of signals intended to attract immune cells. In a youthful, healthy metabolism, senescent cells are created constantly and quickly destroyed. In older people, more senescent cells are created and the processes of destruction become less efficient. Senescent cells accumulate, and their inflammatory signaling degrades tissue and organ function. This accumulation is one of the causes of degenerative aging.

In this sense, chemotherapy and radiotherapy cause accelerated aging. That is a considerably better option than death by cancer, but it may soon be reversible, rather than a fact of life than one must accept. Senolytic therapies capable of selectively destroying some fraction of the senescent cells present in tissue are now a reality, under active development, while some of the early senolytic drugs are readily available on the global market. These have not yet been applied to cancer patients in human trials of their senolytic effects, but that is only a matter of time. The cancer research community is most interested in finding ways to reduce the long-term impact of cancer treatment.

Strategies to Prevent or Remediate Cancer and Treatment-Related Aging

The rapidly aging U.S. population coupled with improved cancer survival rates has led to predictions of unprecedented growth in the number of cancer survivors over the next decade. Unfortunately, many modalities used to cure or control cancer damage healthy tissue, leading rate of functional decline) or accentuate the aging process (e.g., paralleled "normal" aging trajectory with weakened reserve). Data suggests that cancer survivors treated with adjuvant therapies are at risk for early onset of multimorbidity commonly seen in older patients. Estimates indicate that up to 85% of adult cancer survivors and 99% of adult survivors of childhood cancer live with cancer- and treatment-related comorbidities, including frailty, sarcopenia, cognitive impairment, and/or subsequent neoplasms. Adult cancer survivors report engaging in healthy behaviors at levels similar to adults with no history of cancer, and are more likely to adhere to physical activity recommendations. However, there are limited data on how physical activity and other strategies mitigate age-related conditions for cancer survivors.

Aging involves multifaceted, interdependent biological processes that can be altered by cancer and its treatments. The Geroscience Hypothesis postulates that many age-related conditions can be slowed or delayed by targeting hallmarks of aging (e.g., genomic instability, stem cell exhaustion, cellular senescence, inflammation, mitochondrial dysfunction, and epigenetic alterations). Given the complementarity of hallmarks that undergird aging, cancer, and cancer treatments, geroscience-guided interventions might delay or avert the age-related conditions observed in cancer survivors.

To consider emerging strategies that might prevent, mitigate or reverse cancer- and treatment-related aging consequences, the National Cancer Institute (NCI) convened the second of two think tanks under the Cancer and Accelerated Aging: Advancing Research for Healthy Survivors initiative. Emphasis was placed on therapies linked to age-related conditions or underlying aging processes (hallmarks of aging) that could be potential targets for interventions. Although several age-related processes provide potential targets for interventions, meeting discussions focused on cellular senescence. Cellular senescence is a cell fate that includes an irreversible proliferative arrest. Senescent cells accumulate in multiple tissues, and interestingly, transplanting small numbers of senescent cells into young animals induces frailty and age-related disease. Senescent cells also develop a pro-inflammatory senescence-associated secretory phenotype (SASP) that can disrupt tissue and immune function and create a permissive microenvironment for cancer growth.

Senescent cells are a promising target for aging interventions since these cells do not divide and can be eliminated by intermittent dosing using drugs with short half-lives. The SASP is also modifiable: it can be up- or down-regulated by hormones, pathogens, and drugs. Rapamycin, a mTOR inhibitor, is a promising agent that has been implicated in both aging and senescence. Rapamycin fed to older mice was shown to delay aging and extend lifespan. Senolytics have also achieved success in recent pre-clinical studies; notably, several senolytics are repurposed cancer drugs. The first trial in humans, a pilot, open-label study of dasatinib plus quercetin for idiopathic pulmonary fibrosis, a progressive, fatal, senescence-driven disease, was recently published. After nine doses over three weeks, participants showed improved physical function one-week later. If shown to be safe and effective in larger trials, the hope is that mTOR inhibitors and senolytics can be tested as preventatives of age-related conditions in cancer populations. Research is needed to determine the safety and efficacy of dosing intervals, and systemic, as opposed to local, administration.

SENS Research Foundation here explains why COVID-19, like near all infectious disease, is far worse for the old. It isn't just a matter of the decline of immune function, though that is the bulk of it. Older people have a greater burden of damage and dysfunction that makes them less resilient in many other ways. Rising mortality due to infectious disease with age is the result of both (a) a greater likelihood of severe infection due to immune aging, and (b) that the individual is less likely to survive a severe infection due to general frailty. Tens of thousands die every year in the US from seasonal influenza; that is largely ignored, taken as a fact of life when considered at all. But the research and medical communities are on the verge of being able to reverse the consequences of aging, to develop rejuvenation therapies that will improve immune function and resilience in the old. This work needs greater support than it presently receives if we are to see significant progress over the next decade.

Through all the daily updates on the sick and the dead, on testing and hospital capacity and changing public health guidance, there remains one constant: by far the greatest predictor of death from the COVID-19 pandemic is age. The so-called comorbidities predisposing patients to death from COVID-19 - chronic lung diseases, damaged kidneys and hearts, high blood pressure, diabetes - are themselves aspects of aging, erupting in their distinctive ways in particular tissues. Flattening this "demographic curve" of degenerative aging would reduce COVID-19 to a disease similar in impact to an average recent flu season (and make future flu seasons less deadly), while also putting an end to the staggering toll of age-related death and debility that ticks on in the background even now, day in and day out, pandemic or none.

The most obvious link between aging and COVID-19 is the aging of the immune system, or immunosenescence. Older people mount a much weaker and less complete immune response to both infection and vaccine, even as they suffer increasingly from overactive parts of the immune response, including autoimmunity and chronic inflammation. In today's pandemic, COVID-19 patients suffer from an exhaustion of natural killer (NK) and CD8+ ("killer") T-cells. Whereas T-cells and B-cells are specialists, focused on eliminating specifically-identified threats (such as cells infected with specific viruses), NK cells are sentinels patrolling the perimeter of a military camp, on the lookout for anything that looks like it doesn't belong. Long before the pandemic hit, we knew that NK cells lose much of their effectiveness with age, meaning that aging people already come into the fight against infections like SARS-CoV-2 with these critical early responders weakened.

We've known for a while that the age-related loss of lung function is a massive driver of risk of death from pneumonia. Aging people not only have fewer functional alveoli available, but progressively lose the ability to inhale and exhale deeply to compensate for alveoli taken offline by the infection. Continuing research suggests that eliminating senescent cells in the lung may preserve and restore youthful lung function, leaving the lungs better prepared to endure the attack of the SARS-CoV-2 virus and other causes of pneumonia. Senolytic drugs, which selectively kill senescent cells, have been shown to reverse lung fibrosis and other tissue fibrosis in aging mice. Studies in aging mice demonstrate that ablating senescent cells restores youthful lung compliance, suggesting an opportunity to do the same with other senescent-cell elimination strategies, such as restoring the ability of NK cells to eliminate them from tissues.

Like the pandemic, aging touches all of us. It creeps silently through our tissues, progressively crippling our minds and bodies, and eventually killing us if we don't die first of accident, violence, or other abrupt age-independent causes. In COVID-19, the damage caused by aging is the largest factor in determining who lives and who dies, even if the trigger was pulled by a virus spread by globalization. The need for rejuvenation biotechnologies as part of medicine has never been clearer, and so we strengthen our resolve. Restoring our cells and tissues to youthful vigor will allow us to step out of our ancient lockdown and into a bright future.

Link: https://www.sens.org/covid-19-and-aging/

Raised blood pressure with age, hypertension, strongly correlates with cardiovascular disease risk and overall mortality. Hypertension is an important downstream mechanism in aging, a way in which low level biochemical damage - such as cross-linking that stiffens blood vessel walls, or inflammation that produces dysfunction in smooth muscle cells - gives rise to pressure damage to sensitive tissues throughout the body. Hypertension accelerates the progression of atherosclerosis, the development of fatty deposits that weaken and narrow blood vessels, and is associated with a greater risk of atrial fibrillation, an abnormal heart rhythm. This latter correlation may be due to the way in which hypertension produces changes in the structure of the heart, such as a growth and weakening of heart muscle.

Intensive blood pressure control may reduce the risk of atrial fibrillation (AFib), an irregular heartbeat that can lead to serious complications such as stroke, heart failure, and heart attacks. Researchers found that lowering a systolic blood pressure to less than 120 resulted in a 26% lower risk of AFib compared to systolic blood pressure of less than 140.

This analysis, using data from the National Institutes of Health Systolic Blood Pressure (SPRINT) trial, included 8,022 study participants who were randomized into one of two groups: 4,003 participants in an intensive blood pressure control group (target less than 120 mm Hg) and 4,019 participants in a standard lowering group (target less than 140 mm Hg).

Participants were followed for up to five years. During that time, only 88 AFib cases occurred in the intensive blood pressure lowering group while 118 cases occurred in the standard blood pressure lowering group. Researchers showed that the benefit of intensive blood pressure lowering on reducing the risk of AFib was similar in all groups of the participants regardless of sex, race, or levels of blood pressure.

Link: https://www.eurekalert.org/pub_releases/2020-05/wfbm-ibp050120.php

Genetic studies of the past twenty years have quite effectively ruled out the idea that genetic variation has a meaningful impact on life span in the overwhelming majority of people. To a first approximation, there are no longevity genes. Rather there is a mosaic of tens of thousands of tiny, situational, interacting effects, that in aggregate produce an outcome on health that is far smaller than the results of personal choice in health and lifestyle. Near the entirety of the effects that your parents have on your health and life span stems from their influence on the important choices - whether you smoke, whether you get fat, whether you exercise.

But this is not to say that there are no longevity genes. It only constrains our expectations on their rarity, just as human demographics constrains our expectations on how large an effect size is plausible. Big databases and modern data mining can still miss rare variants and mutations. There is the example of the single family of PAI-1 loss of function mutants who might live seven years longer than their peers - possibly as a result of the influence of PAI-1 on the burden of cellular senescence. One might also suspect that the exceptional familial longevity of some Ashkanazi Jews is simply too much for good lifestyle choice to explain, though there no single variant really stands out after many years of assessment.

The commentary here notes recent research into rare variants and life span that, once again, fails to find a sizable contribution to longevity or its inheritance. At some point, we must accept that genetics is most likely not a direct and easy path to enhanced human longevity. It is an important tool in the toolkit, enabling therapies for a range of uses, but the goal of a modest adjustment to a few genes that produces an altered metabolism that yields significant gains in longevity (with minimal side-effects) may be a mirage. Time will tell.

Aging: Searching for the genetic key to a long and healthy life

For centuries scientists have been attempting to understand why some people live longer than others. Individuals who live to an exceptional old age - defined as belonging to the top 10% survivors of their birth cohort - are likely to pass on their longevity to future generations as an inherited genetic trait. However, recent studies suggest that genetics only accounts for a small fraction (~10%) of our lifespan. One way to unravel the genetic component of longevity is to carry out genome-wide association studies (GWAS) which explore the genome for genetic variants that appear more or less frequently in individuals who live to an exceptional old age compared to individuals who live to an average age. However, the relatively small sample sizes of these studies has made it difficult to identify variants that are associated with longevity.

The emergence of the UK Biobank - a cohort that contains a wide range of health and medical information (including genetic information) on about 500,000 individuals - has made it easier to investigate the relationship between genetics and longevity. Although it is not yet possible to study longevity directly with the data in the UK Biobank, several GWAS have used these data to study alternative lifespan-related traits, such as the parental lifespan and healthspan of individuals (defined as the number of years lived in the absence of major chronic diseases). These studies have been reasonably successful in identifying new genetic variants that influence human lifespan, but these variants can only explain ~5% of the heritability of the lifespan-related traits.

The GWAS have only focused on relatively common genetic variants (which have minor allele frequencies (MAFs) of ≥1%), and it is possible that rare variants might be able to explain what is sometimes called the 'missing heritability'. Now researchers report how they analyzed data from the UK Biobank and the UK Brain Bank Network (which stores and provides brain tissue for researchers) to investigate how rare genetic variants affect lifespan and healthspan.

One type of rare genetic variant, called a protein-truncating variant, can dramatically impact gene expression by disrupting the open reading frame and shortening the genetic sequence coding for a protein. The team calculated how many of these rare protein-truncating variants, also known as PTVs, were present in the genome of each individual, and found ultra-rare PTVs (which have MAFs of less than 0.01%) to be negatively associated with lifespan and healthspan. This suggests that individuals with a small number of ultra-rare PTVs are more likely to have longer, healthier lives. This work is the first to show that rare genetic variants play a role in lifespan-related traits, which is in line with previous studies showing rare PTVs to be linked to a variety of diseases. However, these variants only have a relatively small effect on human lifespan and cannot fully explain how longevity is genetically passed down to future generations.

Memory function declines with age. Some part of this is the result of outright structural damage in the brain, caused by the periodic rupture of small blood vessels that kills a small volume of tissue - a form of damage that proceeds that much more rapidly in hypertensive individuals, for all of the obvious reasons. But this is far from the only form of structural change in the brain. More subtle processes of damage and adaptation to damage also take place. Researchers here assess what can be done with modern tools in order to correlate structural change with cognitive decline.

Aging, even in the absence of clear pathology of dementia, is associated with cognitive decline. Neuroimaging, especially diffusion-weighted imaging, has been highly valuable in understanding some of these changes in live humans, non-invasively. Traditional tensor techniques have revealed that the integrity of the fornix and other white matter tracts significantly deteriorates with age, and that this deterioration is highly correlated with worsening cognitive performance. However, traditional tensor techniques are still not specific enough to indict explicit microstructural features that may be responsible for age-related cognitive decline and cannot be used to effectively study gray matter properties.

Here, we sought to determine whether recent advances in diffusion-weighted imaging, including Neurite Orientation Dispersion and Density Imaging (NODDI) and Constrained Spherical Deconvolution, would provide more sensitive measures of age-related changes in the microstructure of the medial temporal lobe. We evaluated these measures in a group of young (ages 20-38 years old) and older (ages 59-84 years old) adults and assessed their relationships with performance on tests of cognition.

We found that the fiber density (FD) of the fornix and the neurite density index (NDI) of the fornix, hippocampal subfields, and parahippocampal cortex, varied as a function of age in a cross-sectional cohort. Moreover, in the fornix and hippocampal subields DG/CA3 and CA1, these changes correlated with memory performance, even after regressing out the effect of age, suggesting that they were capturing neurobiological properties directly related to performance in this task.

These measures provide more details regarding age-related neurobiological properties. For example, a change in fiber density could mean a reduction in axonal packing density or myelination, and the increase in NDI observed might be explained by changes in dendritic complexity or even sprouting. These results provide a far more comprehensive view than previously determined on the possible system-wide processes that may be occurring because of healthy aging and demonstrate that advanced diffusion-weighted imaging is evolving into a powerful tool to study more than just white matter properties.

Link: https://doi.org/10.3389/fnagi.2020.00094

Much of the work that the research community conducts on age-related disease is similar to the example here: attempting to pick apart the proximate causes of pathology in an altered, aged, diseased cellular metabolism. This is far removed from root causes, and thus presents only limited options for the development of beneficial therapies. The biochemistry of any age-related disease is enormously complex in its details, and manipulating any one part of it still leaves all of the rest to progress and cause issues. Since age-related diseases are the downstream result of a less complex set of root causes, it makes much more sense to investigate the root causes. Unfortunately, this remains a comparatively unpopular strategy in the research community.

Osteoarthritis (OA) is a disease with high morbidity, which mainly afflicts the weight-bearing joints, such as the hips and knees, and causes physical disability. However, the precise pathogenesis of OA has not been detailed completely. Research showed that chondrocyte autophagy, as a self-protective mechanism, has been considered as a potential target for recuperating chondrocytes viability and then suppressing the progression of OA. Cellular dysfunction and death often occur when the capacity of endoplasmic reticulum could not bear the protein folding under prolonged endoplasmic reticulum stress (ERs). Hence, the occurrence of ERs would aggravate OA severity. The effects of autophagy and ERs on osteoarthritis remain to be further explored.

MicroRNAs (miRNAs) have been suggested to participate in regulating gene expression after transcription in OA. These small regulators serve vital function in various biological processes. Accumulating research has suggested that some miRNAs had regulatory effect in the formation and process of OA. For instance, miR-155 inhibits autophagy in chondrocytes by regulating autophagy proteins expression. MiR-375 was also found to be connected with cell autophagy. However, few researchers have explored the role of miR-375 in OA.

In the current research, we analyzed the differentially expressed mRNAs and miRNAs between OA and normal cartilage tissues by analyzing microarray datasets. In human samples, we discovered that miR-375 was overexpressed in OA, while ATG2B was conspicuously down-regulated in pathological OA articular cartilage tissues. In vitro, miR-375 inhibited autophagy and enhanced ERs of chondrocytes by suppressing the expression of ATG2B. Simultaneously, apoptosis of chondrocytes was promoted by miR-375 mimics. Furthermore, OA mice model induced by destabilization of the medial meniscus (DMM) surgery in the right knee was established and verified the function of miR-375 on exacerbating OA. Therefore, miR-375 could be a potential target for OA treatment.

Link: https://doi.org/10.18632/aging.103073

Much of the signaling that passes between cells is carried in extracellular vesicles, small membrane-wrapped packages of molecules. There are numerous classes of such vesicle, varying in size, such as microvesicles and exosomes. The study of vesicles has expanded considerably in recent years, as they are much easier to work with than cells, and their use is applicable to many therapeutic goals.

For example, most cell therapies presently in use produce their benefits via the signaling that is generated by transplanted cells in the short period of time before they die. Cells can largely be replaced with extracellular vesicles in this scenario, leading to a much simpler logistic chain for the therapy. Further, extracellular vesicles can be engineered to carry specific molecules into cells, a form of vector that is easier to manufacture and manage than many of the other present options.

Diagnostics and metrics may also benefit considerably from a closer look at extracellular vesicles. Vesicles are present in blood samples, and their contents and composition is, in principle, a reflection of the state of health and aging. Senescent cells, for example, produce quite a different mix of vesicles and vesicle contents in comparison to normal cells. In the same way that biomarkers are constructed from DNA methylation and protein levels, extracellular vesicle analysis may present another path to assays that can quantitatively assess the progression of aging and disease.

Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature

Advancing age is associated with declining muscle mass, function, and strength, a condition referred to as sarcopenia which increases the risk of incurring negative health-related outcomes. No effective pharmacological treatments are currently available to prevent, delay, or treat sarcopenia, which is mostly due to the incomplete knowledge of the underlying pathophysiology. To further complicate the matter, at the clinical level, sarcopenia shows remarkable overlap with frailty, a "multidimensional syndrome characterized by a decrease in physiological reserve and reduced resistance to stressors", often envisioned as a pre-disability condition. Hence, the two conditions have been merged into a new entity, referred to as physical frailty and sarcopenia (PF&S).

Mitochondrial dysfunction and sterile inflammation are invoked among the pathogenic factors of PF&S. Derangements at different levels of the mitochondrial quality control machinery have been reported in older adults with PF&S. However, whether and how cell-based alterations may spread at the systemic level and impact muscle homeostasis is presently unknown. One of the mechanisms by which cells communicate with each other involves a conserved delivery system based on the generation and release of extracellular vesicles (EVs). This shuttle system also contributes to degradative pathways responsible for eliminating oxidized cell components, including mitochondria, by establishing inter-organelle contact sites. As such, the generation and release of mitochondrial-derived vesicles (MDVs) may represent a complement to mitochondrial quality control systems.

Cell-free mitochondrial DNA (mtDNA) has been identified among the molecules released within exosomes that may act as damage-associated molecular patterns (DAMPs). However, whether and how this mechanism is in place in the setting of PF&S is unexplored. In the present study, we purified small extracellular vesicles (sEVs) from older adults with and without PF&S, quantified their amount, and characterized their content for the presence of mitochondrial components. Our results show a greater amount of sEVs in serum of PF&S participants compared with non-PF&S controls. A lower protein expression of CD9 and CD63 was found in the exosome fraction purified from participants with PF&S. These observations are in keeping with the heterogenous composition of exosomes themselves, likely reflecting a different vesicle trafficking regulation.

Lower levels of the mitochondrial components ATP5A (complex V), NDUFS3 (complex I), and SDHB (complex II) were found in participants with PF&S. With the intent of preserving mitochondrial homeostasis, mitochondrial hyper-fission segregates severely damaged or unnecessary organelles that are subsequently disposed via mitophagy. However, mitochondrial-lysosomal crosstalk may dispose mildly oxidized mitochondria via MDV release. Such a mechanism may therefore restore mitochondrial homeostasis before whole-sale organelle degradation is triggered. Though, in the case of defective mitophagy or disruption of the mitochondrial-lysosomal axis, accrual of damaged mitochondria, misfolded proteins, and lipofuscin may occur as a result of inefficient cellular quality control. Therefore, the increased sEV secretion in participants with PF&S might reflect the cell's attempt to extrude dysfunctional mitochondria. However, the reduced secretion of MDV in the same participant group may indicate that mitochondrial quality control is impaired or that the damage to mitochondria is too severe to be disposed via MDVs.

The field of biotechnology is churns with inventive technology demonstrations; this is an era of creativity, unleashed by a rapid advance in knowledge and capabilities. Here, researchers are presented with the challenge of achieving sustained beneficial activation of transplanted stem cells, where culturing the cells with activating signal molecules prior to transplantation produces only a transient effect. They solve the problem by tethering the signal molecules to the stem cell surfaces; the transplanted cells will continue to be stimulated by this signal for as long as they survive. Like all of the best ideas, it is entirely obvious, but only in hindsight.

Muscle ischemia, or damage to muscle from limited oxygen or blood supply, can result from multiple causes, such as injury to a limb or peripheral artery disease. Stem cells derived from a patient's own fat tissue are known to produce factors that prompt new blood vessels to grow into the damaged muscle, restoring oxygen and nutrients, and to modulate inflammation in the damaged tissues. However, in vivo experiments have shown limited benefits, as the stem cells' activity seems to decline after injection into the muscle.

A molecule naturally produced in the body called tumor necrosis factor alpha can spur the stem cells to secrete more of the desired factors. Other studies have tried incubating the cells with TNF-alpha before injection, but the effects fade quickly. Researchers decided to try tethering the TNF-alpha directly to the stem cells, creating nanostimulators - nanoparticles laced with TNF-alpha. The nanoparticles bind to a receptor on the surface of the stem cells, providing localized, targeted, and extended delivery of TNF-alpha.

The researchers tested their approach on mice with surgically induced ischemia in one of their hind legs. They isolated the stem cells from fat tissue, mixed them with the nanostimulators and injected them locally to the mice's affected legs. The researchers saw increased blood flow and oxygen levels in the ischemic legs. They also witnessed improvements in mobility - the treated mice could walk longer distances and their legs were stronger.

Link: https://news.illinois.edu/view/6367/808373

Researchers here report on development of a nanoparticle that sweeps up the amyloid-β associated with Alzheimer's disease, preventing it from forming aggregates. When stuck to the nanoparticle, amyloid-β will not generate the harmful biochemistry that arises as a consequence of the formation of aggregated protein structures. This is an interesting approach to reducing levels of amyloid-β, albeit at a very early stage in development. As always, one must note that there is considerable debate over whether amyloid-β clearance is either the right approach to Alzheimer's disease, or sufficient in and of itself to prevent pathology. Amyloid-β aggregation is clearly harmful, the evidence is plentiful on that front, but it is possible that its presence is a side-effect of a more dominant disease mechanism, such as, for example, chronic inflammation derived from persistent infection.

People who are affected by Alzheimer's disease have a specific type of plaque, made of self-assembled molecules called β-amyloid (Aβ) peptides, that build up in the brain over time. Researchers have developed an approach to prevent plaque formation by engineering a nano-sized device that captures the dangerous peptides before they can self-assemble. The researchers covered the surface of the new nanodevice with fragments of an antibody that recognizes and binds to the Aβ peptides. The surface of the nanodevice is spherical and porous, and its craters maximize the available surface area for the antibodies to cover. More surface area means more capacity for capturing the sticky peptides.

A full antibody molecule can be up to a few dozen nanometers long, which is big in the realm of nanotechnology. However, only a fraction of this antibody is involved in attracting the peptides. To maximize the effectiveness and capacity of the nanodevices, researchers produced tiny fragments of the antibodies to decorate the nanodevice's surface. The scientists constructed the base of the porous, spherical nanodevices out of silica, a material that has long been used in biomedical applications due to its flexibility in synthesis and its nontoxicity in the body. Coated with the antibody fragments, the nanodevices capture and trap the Aβ peptides with high selectivity and strength.

The scientists tested the effectiveness of the devices by comparing how the peptides behaved in the absence and presence of the nanodevices. These studies supported the case that the nanodevices sequester the peptides from the pathway to aggregation by more than 90 percent compared to the control silica particles without the antibody fragments. However, the devices still needed to demonstrate their effectiveness and safety within cells and brains.

Link: https://www.anl.gov/article/nanodevices-for-the-brain-could-thwart-formation-of-alzheimers-plaques

Killing cells is easy. Killing only the cells that you want to kill, while leaving all other cells untouched, is very much more challenging. The ability to do this is fundamental to much of the future of medicine, however. The aging body contains many cell populations that cause significant harm and should be removed, including misconfigured T cells, age-associated B cells, precancerous cells, and of course senescent cells of many different types. Great benefits to health and longevity might be obtained via efficient means of targeting that enable therapies to only destroy unwanted, harmful cells.

This point is well illustrated by present efforts to selectively destroy senescent cells. Today's open access paper is one of a number of recent publications that focus on using galactose conjugation to produce prodrugs that are highly selective to senescent cells. Senescent cells produce a lot of β-galactosidase, a protein that acts to strip galactose from other molecules. It is thus possible to combine any one of a range of toxic cell-killing compounds with galactose to produce molecules that are entirely innocuous until they encounter β-galactosidase, making the therapy very specific to senescent cells.

Researchers have tried this approach with the overly toxic senolytic drug navitoclax, with some success, but one really doesn't have to be clever about the drug used. In principle any of the cytotoxic compounds employed widely in the cancer research community will work. Thus other groups have used duocarmycins, while the researchers noted here instead chose gemcitabine, and a long list of alternative options exist beyond these.

Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice

Previous studies have shown that compounds termed 'senolytics' could kill senescent cells. Reported senolytics target anti-apoptotic pathways, which are up-regulated to inhibit apoptosis in senescent cells. These senolytics have been reported to eliminate certain types of senescent cells and have shown the potential to improve physiological function in several tissues. However, senolytic drugs have significant limitations in killing senescent cells in terms of specificity and broad-spectrum activity because of the dynamic and highly heterogeneous nature of the senescence program, which leads to the varying sensitivity of different types of senescent cells to current senolytic drugs. To overcome these challenges, it is highly demanded to develop a new strategy that permits selectively deleting senescent cells in a wide spectrum of cell types or tissues for anti-aging interventions.

To specifically target senescent cells, we focused on one primary characteristic of senescent cells - the increased activity of lysosomal β-galactosidase, exploited as senescence-associated β-galactosidase (SA-β-gal). Notably, SA-β-gal in diverse types of senescent cells is one widely used marker for identifying senescence in vitro and in vivo, which is linked to the increased content of lysosomes. Therefore, we hypothesized that lysosomal β-gal could be utilized for the design of a galactose-modified prodrug to target senescent cells in a broader spectrum. This prodrug could be processed into a cytotoxic compound by β-gal and subsequently delete senescent cells in a specific manner, a strategy that could overcome the limitations of current senolytic drugs.

Here, we designed a new prodrug, SSK1, that was specifically cleaved by lysosomal β-gal into cytotoxic gemcitabine and induced apoptosis in senescent cells. This prodrug eliminated both mouse and human senescent cells independent of the senescence inducers and cell types. In aged mice, our compound reduced SA-β-gal-positive senescent cells in different tissues, decreased senescence- and age-associated gene signatures, attenuated low-grade chronic inflammation, and improved physical function.

While SA-β-gal is widely used as a marker of cellular senescence, its elevated activity can be found in some other cells such as activated macrophages. These SA-β-gal-positive macrophages can be harmful and have been found to accumulate in injured and aged tissues contributing to chronic inflammation. Importantly, we have shown that SSK1 decreases the number of SA-β-gal-positive macrophages in injured lungs and aged livers, which is consistent with our observation of reduced secretion of chronic inflammation-related cytokines. Therefore, eliminating macrophage accumulation by SSK1 might reduce chronic inflammation and benefit aged organisms.

The ionome is the elemental composition of a tissue, organ, or individual. This composition changes over the course of aging, and may do so in ways that allow the production of an aging clock, a measure of chronological or physiological age. This line of development adds to work on the well-known epigenetic clocks, proteomic clocks, and other assessments of age constructed from algorithmic compositions of simple biomarkers. At the end of the day, all of these approaches need a great deal more validation if they are to be used as originally intended, as a way to rapidly assess potential rejuvenation therapies and thus speed up the field. Since it remains quite unclear as to what exactly these clocks measure, meaning which processes of aging cause the clock numbers to change, the results are not yet actionable.

Aging involves coordinated yet distinct changes in organs and systems throughout life, including changes in essential trace elements. However, how aging affects tissue element composition (ionome) and how these changes lead to dysfunction and disease remain unclear. Here, we quantified changes in the ionome across eight organs and 16 age groups of mice. This global profiling revealed novel interactions between elements at the level of tissue, age, and diet, and allowed us to achieve a broader, organismal view of the aging process. We found that while the entire ionome steadily transitions along the young-to-old trajectory, individual organs are characterized by distinct element changes.

The ionome of mice on calorie restriction (CR) moved along a similar but shifted trajectory, pointing that at the organismal level this dietary regimen changes metabolism in order to slow down aging. However, in some tissues CR mimicked a younger state of control mice. Even though some elements changed with age differently in different tissues, in general aging was characterized by the reduced levels of elements as well as their increased variance. The dataset we prepared also allowed to develop organ-specific, ionome-based markers of aging that could help monitor the rate of aging. In some tissues, these markers reported the lifespan-extending effect of CR. These aging biomarkers have the potential to become an accessible tool to test the age-modulating effects of interventions.

Link: https://doi.org/10.1111/acel.13119

The mTOR inhibitor rapamycin slows the progression of aging in mice. The may largely be a result of upregulated autophagy, as is the case for many other means of slowing aging in short-lived species, including calorie restriction. If an intervention slows aging generally, the odds are fairly good that any specific aspect of aging will also be slowed. Here, researchers show that rapamycin treatment improves the outlook for age-related periodontitis in mice.

Periodontal disease, also known as gum disease, is a common problem in older adults that causes painful inflammation, bone loss, and changes in the good bacteria that live in the mouth. Yet there are no treatments available beyond tooth removal and/or having good oral hygiene. Rapamycin is an immune-suppressing drug currently used to prevent organ rejection in transplant recipients. Previous studies in mice have also suggested that it may have life-extending effects, which has led to interest in studying the drug's effects in many age-related diseases.

To find out if rapamycin might slow periodontal disease, researchers added the drug to the food of middle-aged mice for eight weeks and compared their oral health with untreated mice of the same age. Similar to humans, mice also experience bone loss, inflammation, and shifts in oral bacteria as they age. Using a 3D-imaging technique called micro-computed tomography, the team measured the periodontal bone, or bone around the tooth, of the rapamycin-treated and untreated mice. They showed that the treated mice had more bone than the untreated mice, and had actually grown new bone during the period they were receiving rapamycin.

The work also showed that rapamycin-treated mice had less gum inflammation. Genetic sequencing of the bacteria in their mouths also revealed that the animals had fewer bacteria associated with gum disease and a mix of oral bacteria more similar to that found in healthy young mice. While rapamycin is already used to treat certain conditions, it can make people more susceptible to infections and may increase their risk of developing diabetes, at least at the higher chronic doses typically taken by organ transplant patients. Clinical trials in humans are needed to test whether rapamycin's potential oral health and other benefits outweigh its risks.

Link: https://elifesciences.org/for-the-press/89774f76/immune-regulating-drug-improves-gum-disease-in-mice

Age-related neurodegeneration is characterized by the aggregation of a small number of proteins, including α-synuclein, that can become altered in a manner that encourages other molecules of the same protein to alter in the same way. These altered forms of protein precipitate to form structures solid fibrils and deposits, surrounded by a halo of toxic biochemistry that impairs cell function. Today's open access paper explores just one of the ways in which α-synuclein harms cells, in this case by downregulating the operation of autophagy.

Autophagy is the name given to a collection of cellular maintenance processes that are particularly important in long-lived cells such as the neurons of the central nervous system. Autophagy recycles damaged and unwanted structures and proteins in the cell. When it falters, cells accumulate dysfunctional components and suffer accordingly. Unfortunately, evidence suggests that the efficiency of autophagy declines with age, though the underlying causes of this issue are poorly understood. Increases in autophagy are thought to be responsible for the extension of life produced by the practice of calorie restriction, as well as many other interventions shown to improve health and extend health in

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

Parkinson's disease (PD) is a common late onset progressive neurodegenerative disease most characterized by movement disorder resulting from the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). In addition, PD is also characterized by the presence of protein inclusions known as Lewy bodies (LB) and Lewy neurites (LN), which are composed of aggregated α-synuclein (αS), in multiple neuronal populations. While the etiology of PD is unknown in most cases, αS abnormalities are mechanistically linked to PD pathogenesis as mutations in αS cause PD in a small number of familial PD pedigrees. Currently, how αS abnormalities cause neuronal dysfunction and degeneration is not fully understood. However, studies have implicated oxidative stress in the pathogenesis of PD and dysfunction in proteostasis. While oxidative stress in neurons has complex and multifaceted effects, recent reports suggest that activation of c-Abl, a non-receptor tyrosine kinase, can be stimulated by oxidative stress. And thus, may be linked to the pathogenesis of PD, Alzheimer's disease (AD) and other neurodegenerative diseases.

c-Abl is a tyrosine kinase known to be activated by cellular stressors, such as oxidative stress and DNA damage. c-Abl also functions to regulate many fundamental cellular processes, such as cell survival, migration, and growth factor signaling. Emerging studies implicate aberrant c-Abl activity in neurodegenerative disease. In PD, c-Abl is activated in regions showing DAergic neurodegeneration, such as the striatum and SNpc, and inactivates parkin by phosphorylation. Significantly, c-Abl activation is linked to αS pathology as increased αS expression in cells and transgenic (Tg) mice was associated with c-Abl activation, and inhibition of c-Abl or the loss of c-Abl expression leads to attenuation of αS levels and/or aggregation. Some of these studies implicate c-Abl as an inhibitor of autophagy. However, it is unknown how c-Abl regulates autophagy.

We show that c-Abl-dependent inhibition of autophagy is p53 dependent, as c-Abl activation in a transgenic mouse model of α-synucleinopathy (TgA53T) and human PD cases are associated with the increased p53 activation. Significantly, active p53 in TgA53T neurons accumulates in the cytosol, which may lead to inhibition of autophagy. Further, both c-Abl and p53 activity is positively associated with mTOR activity and inversely associated with AMPK/ULK1 activity, showing that c-Abl and p53 directly impact the pathways relevant to autophagy regulation. Finally, we show that c-Abl-dependent pathway is a significant target for therapeutic intervention as pharmacological inhibition of c-Abl delays disease onset in two independent Tg mouse models of α-synucleinopathy. Our data identify a novel pathway for regulation of autophagy in α-synucleinopathy and support the development of c-Abl and p53 inhibitors for disease modifying therapies for PD and other α-synucleinopathies.

Hydrogen can scavenge free radical molecules, and thus act as a form of antioxidant. Researchers here demonstrate that in action in nematode worms. Excessive levels of free radicals such as reactive oxygen species are present in older individuals, and this state of oxidative stress contributes to cell and tissue dysfunction. The role of oxidants is a complicated one, however, as they serve as signals to cellular maintenance processes. Alteration in amounts of oxidative stress frequently have counterintuitive results on health and longevity in short-lived laboratory species. Further, the size of the effect in species such as the nematodes used here is small enough that one would expect there to be little benefit to long-lived species such as our own, given that benefits to longevity from all interventions affecting cellular maintenance signaling scale down as species life span increases.

It is well known that hydrogen can effectively scavenge free radicals in vivo or in vitro and exhibit valuable antioxidant activity. Under stress such as ischemia or hypoxia in the brain, heart and other vital organs and tissues, immune cells release a large amount of reactive oxygen species (ROS), while hydrogen can selectively neutralize hydroxyl radicals and peroxynitrites, which are related to the activation of the Nrf2 signaling pathway. Hydrogen-rich saline (HRS) can also reduce the damage to important organs, tissues, and cells caused by oxidative stress. In general, hydrogen has two advantages compared with other antioxidants, such as vitamin A and vitamin C. First, hydrogen can selectively neutralize hydroxyl radicals and nitrite anions. Second, it can quickly reach the area in danger regardless of cellular barrier. The fact that antioxidants have limited therapeutic success may be because most antioxidants cannot reach specific ROS-abundant regions. Thus, hydrogen can be used as an effective antioxidant therapy owing to its ability to diffuse rapidly across cellular membranes, because it can reach and react with cytotoxic ROS and protect against oxidative damage.

The free radical aging theory, which is also called the aging oxidative stress theory, states that aging is caused by normal oxidative metabolism by-products such as ROS. Normally, the antioxidant defense system eliminates ROS, and living organisms are protected from oxidative stress. Therefore, weakening of the antioxidant defense system, which may be caused by several factors, such as aging, will lead to excess oxidative stress and senescence. The detection of hydrogen peroxide (H2O2) further suggests that aging is caused by excess ROS. In C. elegans, genes such as sod-1, sod-4, and sod-5 encode Cu/Zn-SODs, and sod-2 and sod-3 encode Fe/Mn-SODs. Therefore, mutations in sod family genes may impact defense against oxidative stress. In this study, we found that older nematodes have higher ROS levels. Interestingly, after hydrogen treatment, the ROS levels were significantly decreased, and hydrogen could significantly extend the lifespans of the N2, sod-3 and sod-5 mutant strains, by approximately 22.7%, 9.5%, and 8.7%, respectively.

In addition, aging is regulated by a variety of pathways, such as the insulin signaling pathway, the rapamycin target signaling pathway, and the caloric restriction pathway. However, our results showed that the lifespans of the daf-2 and daf-16 strains, in which these pathways are upregulated, were not affected after hydrogen treatment. Based on these data and previous reports that hydrogen is a valuable antioxidant in vitro, lifespan extension by hydrogen is mostly related to ROS levels. It seemed that exogenous hydrogen does not act through the insulin signaling pathway to produce its antiaging effects, which may result from a direct reaction with ROS in vivo.

Link: https://doi.org/10.1371/journal.pone.0231972

Alzheimer's disease is strongly driven by chronic inflammation in brain tissue. Studies in which senescent, inflammatory microglia are removed from the brain strongly suggests this to be the case in the later stages of the condition. Here, researchers use animal models to demonstrate that it may also be the case in the early stages, prior to onset of obvious symptoms of cognitive decline. A view of Alzheimer's disease in which inflammation is the dominant mechanism - resulting from some combination of exposure to pathogens, accumulation of senescent cells, and dysregulation of immune cells due to amyloid-β aggregates - is gathering support these days.

In a new animal study examining Alzheimer's disease, researchers found that disease progression could be slowed by decreasing neuroinflammation in the brain before memory problems and cognitive impairment were apparent. The new findings point to the importance of developing therapies that target very early stages of the disease. In 2011, the National Institute on Aging updated the diagnostic criteria for Alzheimer's disease to reflect its progressive nature. The criteria added a preclinical stage during which brain changes are taking place, but the person is still asymptomatic and, therefore, unaware of his condition. Biomarker profiles could eventually be used to identify people in the disease's early stages who might benefit from early treatments.

"Starting an intervention at the earliest stage of the disease, when cellular and molecular alterations have already been triggered but major damage to the brain has not yet occurred, could offer a way to reduce the number of people who go on to develop full Alzheimer's dementia. However, there have been few studies in animals examining therapeutic strategies that target timepoints before symptoms can be seen."

The researchers designed an animal study to gain a deeper understanding of the role of neuroinflammation in Alzheimer's disease during the pre-symptomatic stage of the disease, which might represent the best time for therapeutic intervention. The study results suggest that rebalancing neuroinflammation in animals that show altered neuroinflammatory parameters could be beneficial. "Our results help demonstrate that neuroinflammation in Alzheimer's disease is an extremely complex phenomenon that can change over the disease's progression and varies based on factors such as affected brain area. We hope that these findings will prompt scientists to further investigate neuroinflammation at the earliest stages of the disease, which may represent an important pharmacological target."

Link: https://www.eurekalert.org/pub_releases/2020-04/eb-reb042220.php

The degree to which interventions targeting different mechanisms associated with longevity might stack or synergize to produce greater gains is a woefully understudied topic. Study of synergies between treatment approaches is in general poorly studied and poorly developed throughout the medical biotechnology community; the incentives in place discourage this sort of work at every level of development. Funding is sparse, and different groups holding intellectual property for different approaches tend not to cooperate with one another. Thus, thirty years in to the modern study of interventions that can extend longevity in laboratory species, whether or not the scores of different approaches synergize, and to what degree, remains largely unexplored and unknown.

For what it is worth, it does seems unlikely that combining three or more marginal effects based on stress response upregulation will produce an outcome worth caring about. Equally, many of the diverse mechanisms demonstrated to modestly slow aging in animal models are just different ways of influencing the same underlying system, and shouldn't be expected to produce synergies. Nonetheless, this area of study is criminally neglected, and this will become ever more an issue as the first narrow rejuvenation therapies are developed, approaches that repair specific forms of underlying damage that are causative of aging, and can thus produce sizable benefits. As an example of one of the few projects of recent years to focus on the foundations needed to discover and develop combinatorial therapies, researchers here establish a database of reported interactions between longevity-associated genes.

SynergyAge

The main goal of the SynergyAge database is to host high-quality, manually curated information about the synergistic and antagonistic lifespan effects of genetic interventions in model organisms. Although our group aims to better understand human aging, data on the effect of multiple genetic manipulations in humans is inexistent (for obvious reasons). As such, SynergyAge relies on reporting combinations of genetic manipulations from model organisms only.

Currently three organisms are included, worms, flies and mice, with data curated so far coming mostly from worms. This bias is mainly due to a easier methodology of modulating gene expression in worms (e.g. through RNAi) but also due to lifespan screening in worms being much faster (worms live much less and are a friendly model for this type of studies). All entries in SynergyAge are based on experimentally validated results from peer-reviewed scientific literature and are manually extracted by our database curators.

SynergyAge: a curated database for synergistic and antagonistic interactions of longevity-associated genes

Interventional studies on genetic modulators of longevity have significantly changed gerontology. While available lifespan data is continually accumulating, further understanding of the aging process is still limited by the poor understanding of epistasis and of the non-linear interactions between multiple longevity-associated genes. Unfortunately, based on observations so far, there is no simple method to predict the cumulative impact of genes on lifespan. As a step towards applying predictive methods, but also to provide information for a guided design of epistasis lifespan experiments, we developed SynergyAge - a database containing genetic and lifespan data for animal models obtained through multiple longevity-modulating interventions.

The studies included in SynergyAge focus on the lifespan of animal strains which are modified by at least two genetic interventions, with single gene mutants included as reference. SynergyAge provides an easy to use web-platform for browsing, searching and filtering through the data, as well as a network-based interactive module for visualization and analysis.

Research groups are eyeing telomere lengthening as a way to improve stem cell function. Telomeres are the caps of repeated DNA sequences at the ends of chromosomes. A little of their length is lost with each cell division, and cells with very short telomeres become senescent or self-destruct. In the vast majority of cells in the body, this is an important part of the Hayflick limit on cellular replication. Stem cells, however, use telomerase to extend their telomeres.

With age average telomere length is reduced. In most cells, this is just a reflection of the balance between the activity of stem cells, delivering new daughter cells with long telomeres, and ongoing cellular replication that shortens telomeres. As stem cell function declines with age, it isn't surprising to see average telomere length decline. In stem cells themselves, however, the situation is more complex. Why exactly they decline in function, and why extending telomeres improves that function, is far from settled. As outlined here, researchers are investigating the regulation of telomere length in stem cells in order to find targets that might lengthen these telomeres and thus improve stem cell function. This might be a safer approach to achieving most of the same goals of telomerase gene therapy, but without the concerns about side-effects that might result from to expression of telomerase throughout tissues.

A new study may offer a breakthrough in treating dyskeratosis congenita (DC) and other so-called telomere diseases, in which cells age prematurely. Using cells donated by patients with the disease, researchers identified several small molecules that appear to reverse this cellular aging process. The compounds identified in the study restore telomeres, protective caps on the tips of our chromosomes that regulate how our cells age. Telomeres consist of repeating sequences of DNA that get shorter each time a cell divides. The body's stem cells, which retain their youthful qualities, normally make an enzyme called telomerase that builds telomeres back up again. But when telomeres can't be maintained, tissues age before their time. A spectrum of diseases can result.

DC can be caused by mutations in any of multiple genes. Most of these mutations disrupt telomerase formation or function - in particular, by disrupting two molecules called TERT and TERC that join together to form telomerase. TERT is an enzyme made in stem cells, and TERC is a so-called non-coding RNA that acts as a template to create telomeres' repeating DNA sequences. Both TERT and TERC are affected by a web of other genes that tune telomerase's action. One of these genes is PARN, important for processing and stabilizing TERC. Mutations in PARN mean less TERC, less telomerase, and prematurely shortened telomeres.

Researchers focused on an enzyme that opposes PARN and destabilizes TERC, called PAPD5. The team first conducted large-scale screening studies to identify PAPD5 inhibitors, testing more than 100,000 known chemicals. They got 480 initial "hits," which they ultimately narrowed to a small handful. They then tested the inhibitors in stem cells made from the cells of patients with DC. The compounds boosted TERC levels in the cells and restored telomeres to their normal length. The team then introduced DC-causing PARN mutations into human blood stem cells, transplanted those cells into mice, then treated the mice with oral PAPD5 inhibitors. The compounds boosted TERC and restored telomere length in the transplanted stem cells, with no adverse effect on the mice or on the ability to form different kinds of blood cells.

In the future, researchers hope to validate PAPD5 inhibition for other diseases involving faulty maintenance of telomeres - and perhaps even aging itself. "We envision these to be a new class of oral medicines that target stem cells throughout the body. We expect restoring telomeres in stem cells will increase tissue regenerative capacity in the blood, lungs, and other organs affected in DC and other diseases."

Link: https://news.harvard.edu/gazette/story/2020/04/study-identifies-potential-drug-treatments-for-telomere-diseases/

The development of atherosclerotic lesions involves the dysfunction of macrophage cells. They are normally responsible for removing lipids from lesions and handing it off to HDL particles to be returned to the liver, but the presence of oxidized lipids causes them to become inflammatory foam cells, packed with lipids and eventually dying to add their mass to the growing lesion. Researchers here study the formation of foam cells in order to better understand the ordering of events. At present the more promising new lines of therapy for atherosclerosis involve ways to make macrophages resilient to the foam cell fate, such as via removal of oxidized lipids. These are still in comparatively early stages of development, however.

Accumulation of lipid-laden (foam) cells in the arterial wall is known to be the earliest step in the pathogenesis of atherosclerosis. There is almost no doubt that atherogenic modified low-density lipoproteins (LDL) are the main sources of accumulating lipids in foam cells. Atherogenic modified LDL are taken up by arterial cells, such as macrophages, pericytes, and smooth muscle cells in an unregulated manner bypassing the LDL receptor. The present study was conducted to reveal possible common mechanisms in the interaction of macrophages with associates of modified LDL and non-lipid latex particles of a similar size.

To determine regulatory pathways that are potentially responsible for cholesterol accumulation in human macrophages after the exposure to naturally occurring atherogenic or artificially modified LDL, we used transcriptome analysis. Previous studies of our group demonstrated that any type of LDL modification facilitates the self-association of lipoprotein particles. The size of such self-associates hinders their interaction with a specific LDL receptor. As a result, self-associates are taken up by nonspecific phagocytosis bypassing the LDL receptor. That is why we used latex beads as a stimulator of macrophage phagocytotic activity. We revealed at least 12 signaling pathways that were regulated by the interaction of macrophages with the multiple-modified atherogenic naturally occurring LDL and with latex beads in a similar manner. Therefore, modified LDL was shown to stimulate phagocytosis through the upregulation of certain genes.

We have identified at least three genes (F2RL1, EIF2AK3, and IL15) encoding inflammatory molecules and associated with signaling pathways that were upregulated in response to the interaction of modified LDL with macrophages. Knockdown of two of these genes, EIF2AK3 and IL15, completely suppressed cholesterol accumulation in macrophages. Correspondingly, the upregulation of EIF2AK3 and IL15 promoted cholesterol accumulation. These data confirmed our hypothesis of the following chain of events in atherosclerosis: LDL particles undergo atherogenic modification; this is accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. This chain of events may explain the relationship between cholesterol accumulation and inflammation. The primary sequence of events in this chain is related to inflammatory response rather than cholesterol accumulation.

Link: https://doi.org/10.3390/ijms21082716

It is interesting to compare today's open access paper on converting the senolytic drug navitoclax into a PROTAC with recent efforts to improve navitoclax by conjugation with galactose. In both cases the objective is to reduce side-effects, but the strategies are quite different. Navitoclax is arguably the worst of the viable first generation senolytic drugs capable of selectively destroying senescent cells in old tissues. Senescent cells accumulate with age and cause great harm via their inflammatory signaling. Removing them has been shown to extend healthy life, reverse aspects of aging, and turn back a wide range of age-related diseases in animal models. Nonetheless, navitoclax is a toxic and unpleasant chemotherapeutic, and in addition to being poorly selective in comparison to more recent senolytic compounds, it also kills platelets to produce thrombocytopenia.

Galactose conjugation is pretty straightforward: link navitoclax with galactose to produce a molecule that is innocuous until the β-galactosidase found in large amounts in senescent cells cleaves away the galactose to reveal navitoclax. Thus the activity of navitoclax is largely restricted to senescent cells, reducing its off-target effects. Making a PROTAC, a proteolysis targeting chimera, is somewhat more complex and needs less of the structure of navitoclax - it is more of an evolution of the compound to produce a new small molecule. In this case, the part of navitoclax capable of binding to Bcl-xl is connected to sequences that cause a cell to degrade the Bcl-xl protein, an activity that will force a senescent cell into apoptosis. This only takes place if the cell has the right molecular machinery to kick off that degradation process, however. Platelets do not have that machinery, and so the PROTAC derived from navitoclax will not activate in platelets. The platelets survive, and thrombocytopenia is evaded.

Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity

ABT263 (also known as navitoclax), a Bcl-2 and Bcl-xl dual inhibitor, is one of the most potent and broad-spectrum senolytic agents identified to date. Bcl-xl inhibition with ABT263 and other small molecular inhibitors induces platelet apoptosis and results in severe thrombocytopenia, which prevents the use of ABT263 and other Bcl-xl specific inhibitors in the clinic - even for cancer patients - because platelets solely depend on Bcl-xl for survival. By contrast, Bcl-2 is dispensable for thrombopoiesis and platelet survival in mice and humans and inhibition of Bcl-2 with ABT199 (also known as venetoclax) does not induce thrombocytopenia. We hypothesize that we can reduce ABT263 on-target toxicity and generate a safer senolytic agent by converting ABT263 into a platelet-sparing Bcl-xl proteolysis-targeting chimera (PROTAC).

PROTACs are bivalent small molecules containing a ligand that recognizes a target protein linked to another ligand that recruits a specific E3 ubiquitin ligase. PROTAC binding induces proximity-induced ubiquitination of the target protein and its subsequent degradation by proteasomes. Importantly, because PROTACs rely on E3 ligases to induce protein degradation, it is possible to achieve cell/tissue selectivity, even when the target proteins are ubiquitously expressed as long as they target the proteins to an E3 ligase that is cell- or tissue-specific.

Here, we report the use of PROTAC technology to reduce ABT263 on-target toxicity by converting ABT263 into PZ15227 (PZ), a Bcl-xl specific PROTAC (Bcl-xl-P), which targets Bcl-xl to the E3 ligase cereblon (CRBN) that is poorly expressed in platelets. We find that PZ is less toxic to platelets but equally or slightly more potent against senescent cells compared with ABT263. These findings provide an approach to reduce on-target toxicity of toxic senolytic agents. With further improvement, Bcl-xl-Ps have the potential to be developed into safer and more effective senolytics than ABT263.

The brain makes use of sensory information in order to form memories. Loss of hearing has an impact on the aging brain, as suggested by the correlation between onset of age-related deafness and onset of dementia. While it is possible that this reflects common processes of neurodegeneration, as age-related deafness appears to result from loss of neural connections between sensory hair cells and the brain, studies such as this one provide evidence for deafness to cause greater loss of function in areas of the brain associated with memory formation.

Brain structures that are essential for the acquisition and encoding of complex associative memories, such as the hippocampus, use spatial sensory information both to generate metric representation of navigable space and to create robust and long-lasting records of spatial experience. The latter is enabled by hippocampal synaptic plasticity, and it has been shown that visuospatial, olfactospatial, and audiospatial experience can be used by the hippocampus to create spatial memories.

Studies of the consequences of loss of visual input and blindness have shown that adaptation occurs as a consequence of extensive reorganization of the cortex that reflects both changes in the affected primary sensory cortex and in other primary and associative sensory areas. One aspect of this that has received little attention is how the cortex and hippocampus functionally adjust to initial loss of input from a specific sensory modality. Recently, we reported that hereditary blindness that becomes manifest in mice within weeks after birth results in massive and progressive reorganization of neurotransmitter receptor expression in the cortex and hippocampus that persists for months after the onset of blindness. This reorganization is accompanied by a profound impairment of hippocampal long-term potentiation (LTP) and debilitation of hippocampus-dependent spatial learning.

Ultimately, both humans and animals recover from this transitional phase. Recent studies in human individuals have suggested, however, that the consequences for cognition of gradual sensory loss are insidious. Age-dependent sensorineural hearing loss (presbycusis) comprises a gradual and cumulative loss of hearing sensitivity. It is closely associated with cognitive decline and is considered a risk factor for dementia.

A causal link between cumulative hearing loss and cognitive decline is currently lacking. In the present study, our goal, therefore, was to explore to what extent a gradual loss of hearing sensitivity can result in cortical reorganization and changes in hippocampal function. The C57BL/6 mouse strain develops cumulative deafness that first becomes manifest at the age of 4 weeks. We show here that widespread changes in plasticity-related neurotransmitter expression become manifest as early as at 2 months of age in C57BL/6 mice. At 4 months of age, neurotransmitter receptor changes occur in both primary sensory and association cortices and also extend to the hippocampus. At this time-point, potent impairments in hippocampal LTP and spatial memory become evident.

The data indicate that gradual hearing loss is accompanied by extensive adaptive changes in the cortex and hippocampus that hinder effective hippocampal information processing and suggest that progressive hearing loss may be causally linked to cognitive decline.

Link: https://doi.org/10.1093/cercor/bhaa061

The common neurodegenerative conditions are characterized by the aggregation of a few types of misfolded or otherwise altered proteins, harmful to cell and tissue function. Each form of protein aggregate is not a process occurring in isolation; their presence and their consequences interact with one another. Neurodegeneration is a holistic process, and the scientific and medical communities carve pieces out of that whole and call them diseases or disease mechanisms. It doesn't do to lose sight of the fact that these neatly boxed classifications are to some degree arbitrary lines in the sand.

Many people with Lewy body diseases (LBDs) such as Parkinson's disease (PD) ultimately develop dementia, and many have amyloid-β (Aβ) plaques and tau tangles. Do they have two diseases at the same time, or is this combination of scourges a unique entity unto itself? Researchers reported that people with PD who carry genetic risk variants for Alzheimer's disease (AD) were more likely to become cognitively impaired. Similarly, AD variants predicted which PD patients harbored Aβ and tau proteopathies in their brains. In people with dementia with Lewy bodies (DLB), Aβ plaques seemed to worsen cognitive decline more than tau tangles did, suggesting an etiology distinct from AD. Although the interactions between α-synuclein, Aβ, and tau still need more clarification, some suggested that therapies targeting Aβ might benefit people with Lewy body diseases.

Studies suggest that Aβ could exacerbate both tau and α-synuclein aggregation in LBD. This may be why Aβ-targeted therapies could benefit people with synucleinopathies. However, anti-Aβ therapies have failed to benefit cognition in people with AD, so why would they work for LBD? In LBDs, Aβ appears to exacerbate both tau tangles and α-synuclein aggregation, either of which could lead to dementia. Targeting Aβ might dismantle this toxic triplet. Second, while Aβ plays the role of instigator in AD, it appears to drive progression throughout the disease process in LBD. Therefore, while ridding the brain of Aβ may be too little, too late, for people with symptomatic AD, it could slow the disease in people with LBD.

Link: https://www.alzforum.org/news/community-news/av-lewy-body-disease-two-diseases-once-or-another-beast-entirely