Fight Aging!

The brain requires a great deal of energy for normal operation. Indeed, parts of the brain, such as the hippocampus, responsible for memory function, clearly operate at the limits of their capacity even in youth. Aging leads to a reduced blood flow to the brain via a number of mechanisms, including heart failure, atherosclerotic narrowing of blood vessels, and loss of capillary density. This has a negative impact on function. Additionally, however, mitochondrial function declines with age. The hundreds of mitochondria present in every cell work to package chemical energy store molecules to power the cell. When this activity falters, it has a similarly negative result on energy-hungry tissues.

A progressive loss of energy provided to cells in the brain, however it comes about, is thought to be one of the contributing causes of neurodegenerative disease. In today's open access paper, researchers discuss the role of mitochondrial dysfunction in one of the common neurodegenerative conditions, Alzheimer's disease. This is an inflammatory condition, in which much of the focus is placed on the formation of toxic protein aggregates, so it is interesting to see how mitochondrial function fits in to this picture. Alzheimer's, like many neurodegenerative conditions, is likely the converging end result of numerous chains of interacting causes and consequences. The Alzheimer's brain is highly dysfunctional, so short of repairing specific forms of dysfunction in isolation and observing the outcome, it is a challenge to identify true contributing causes versus the side-effects of true contributing causes.

Mechanisms of Mitochondrial Malfunction in Alzheimer's Disease: New Therapeutic Hope

Mitochondria play a critical role in neuron viability or death as it regulates energy metabolism and cell death pathways. They are essential for cellular energy metabolism, reactive oxygen species production, apoptosis, Ca++ homeostasis, aging, and regeneration. Mitophagy and mitochondrial dynamics are thus essential processes in the quality control of mitochondria. According to several recent articles, a continual fusion and fission balance of mitochondria is vital in their normal function maintenance. As a result, the shape and function of mitochondria are inextricably linked. This study examines evidence suggesting that mitochondrial dysfunction plays a significant early impact on AD pathology.

Although mitochondrial dysfunction is a typical indication of Alzheimer's disease, it is unclear whether the cellular systems that maintain mitochondrial integrity malfunction, aggravating mitochondrial pathology. Different levels of vigilance and preventive methods are used to reduce mitochondrial damage and efficiently destroy faulty mitochondria to maintain the mitochondrial equilibrium. The form and function of mitochondria are regulated by mitochondrial fusion and fission. In contrast, mitochondrial transit holds mitochondrial dispersion and transports old and damaged mitochondria from distant axons and synapses to the central cell for lysosomal destruction. As the fundamental mechanisms of mitochondrial quality control, several critical properties of mitochondria work in tandem with mitophagy. According to the findings, mitochondrial viability and function are managed by mitochondrial fusion, fission, transport, and mitophagy, forming a complex, dynamic, and reciprocal interaction network.

According to growing evidence, AD brains have disrupted mitochondrial dynamics and aberrant mitophagy, which may interfere with mitochondrial quality control directly or indirectly. Further research into these processes might help us better understand mitochondrial malfunction in Alzheimer's disease. Given the ability to improve some phenotypes by manipulating genes that regulate mitophagy, there is reason to believe that attempting to subvert mitochondrial dynamics, motility unilaterally, and mitophagy will enhance mitochondrial surveillance mechanisms and decrease the neuropathology of Alzheimer's disease, feasibly leading to new treatment strategies.

Many of the interventions shown in animal studies to slow aging involve changes in the mechanisms that respond to nutrient intake. In effect mimicking some fraction of the natural response to a reduced calorie intake. Cells become more frugal, engage in more repair and recycling. Over the long term this extends life span, though to a far greater degree in short-lived species than in long-lived species such as our own. These mechanisms occur in near all species, and have ancient origins. Improved survival in the face of seasonal famine was an early winner in the evolutionary arms race. But a season is a large fraction of a mouse life span, and a small fraction of a human life span, so only the mouse has evolved to exhibit a sizable gain in life span when food is scarce.

The rate of aging and lifespan regulation depend on genetic and non-genetic or environmental factors. A significant amount of data has now established that the environment has a profound effect on lifespan regulation, with diet and stress being predominant factors determining survival, at the cellular, tissue, and organismal levels. Cells perceive nutrients, i.e., amino acids and sugars, through nutrient-responsive pathways that are hard-wired to basic metabolic processes, such as gene transcription, protein translation, proteostasis, and protein degradation rates, mitochondrial function, such as detoxification and respiration, as well as autophagy.

In this review, we provide a framework of knowledge about the role of nutrient-responsive pathways in lifespan and healthspan regulation, such as the Insulin Growth Factor (IGF) and mechanistic Target of Rapamycin (mTOR), and an update on the advancements in this scientific field. We briefly refer to fundamental principles of these pathways. In summary, activation of the related signaling controlled by IGF and mTOR, while beneficial early in life, supporting growth and development, seems detrimental in lifespan and healthspan. While the fundamental molecular players around these pathways - although not fully characterized - are sketched on a satisfactory level within simpler organisms, such as yeasts, D. melanogaster, and C. elegans, additional studies are needed to understand functional links on a genome-wide scale. Moreover, single or combinatorial drug treatments that target specific nutrient-responsive and other signaling pathways that affect growth, have been utilized to test effects on lifespan, as well as in healthspan, such as, amelioration of pathological states that might phenocopy age-related diseases or syndromes.

Nevertheless, genetics, as well as epigenetics, of human aging and the role of diet on human lifespan regulation are still being worked out. The field is utilizing stem cell technologies, patient samples, and organoids to bridge this gap and has found itself mature enough to proceed to large studies and clinical trials using mammalian species close to humans, such as dogs. However, cross-species comparisons reveal differential tempos, not only in differentiation programs but also within fundamental processes, such as proteostasis and protein half-life patterns, that can affect aging processes and lifespan and healthspan. These studies show that the precise, quantitative outcomes in model organisms might differ from conditions in the human body or even in human cohorts. Therefore, although the contribution of model organisms in biogerontology studies is significant in understanding underlying molecular mechanisms, interdisciplinary studies combining genetics, biomarker analyses, diet and drug surveys, and interventions in human populations are now needed within the field.

Link: https://doi.org/10.3390/cells11091568

Molecular waste, such as amyloid-β aggregates, is cleared from the brain via cerebrospinal fluid drainage and other paths such as direct entry into the circulatory system via the blood-brain barrier. A number of recent ventures have focused on the former path, such as Leucadia and EnClear, but here researchers suggest that biochemical changes in later life reduce passage of amyloid-β through the blood-brain barrier from the brain into the circulation. They implicate raised expression of one gene, FMNL2, but it remains to be seen as to (a) why this happens, how raised expression connects to the underlying damage of aging, and (b) how much of the pathology leading into neurodegeneration is mediated by FMLN2 and this pathway for removal of molecular waste from the brain.

A new study found a gene called FMNL2 links cerebrovascular disease and Alzheimer's and suggests changes in FMNL2 activity caused by cerebrovascular disease prevent the efficient clearance of toxic proteins from the brain, eventually leading to Alzheimer's disease. Researchers found FMNL2 in a genome-wide hunt designed to uncover genes associated with both vascular risk factors and Alzheimer's disease. The search involved five groups of patients representing different ethnic groups.

The blood-brain barrier is a semi-permeable, highly controlled border between capillaries and brain tissue that serves as a defense against disease-causing pathogens and toxins in the blood. Astrocytes, a specialized type of brain cell, compose and maintain the structure of the blood-brain barrier by forming a protective sheath around the blood vessel. This astrocyte sheath needs to loosen for the clearance of toxic amyloid - the aggregates of proteins that accumulate in the brain and lead to Alzheimer's disease.

A zebrafish model confirmed the presence of FMNL2 in the astrocyte sheath, which retracted its grip on the blood vessel once toxic proteins were injected into the brain, presumably to allow for clearance. When researchers blocked the function of FMNL2, this retraction did not occur, preventing clearance of amyloid from the brain. The same process was then confirmed using transgenic mice with Alzheimer's disease.

The same process may also occur in the human brain. The researchers studied postmortem human brains and found increased expression of FMNL2 in people with Alzheimer's disease, along with breach of the blood-brain barrier and retraction of the astrocytes. Based on these findings, the researchers propose that FMNL2 opens the blood-brain-barrier - by controlling its astrocytes - and promotes the clearance of extracellular aggregates from the brain. And that cerebrovascular disease, by interacting with FMNL2, reduces the clearance of amyloid in the brain.

Link: https://www.cuimc.columbia.edu/news/missing-link-between-alzheimers-and-vascular-disease-found

It is now well known that many of the negative consequences resulting from chemotherapy and radiotherapy are mediated by a raised burden of senescent cells. One of the goals of cancer therapy is to drive cancerous cells into senescence: better to have senescent cells than cancerous cells! Nonetheless, gaining a greater burden of senescent cells is literally accelerated aging, as these additional senescent cells actively degrade tissue function and create chronic inflammation via their secretions. Thus senolytic therapies should be of great benefit to cancer survivors, removing this harmful side-effect of cancer therapy.

Are all senolytics the same? No, absolutely not. This has already been made quite clear from the work of the past few years. Some approaches are much better than others for differing cell types and origins of cellular senescence. Here, researchers show that navitoclax is a whole lot better than the dasatinib and quercetin combination when it comes to cells made senescent as a result of irradiation. One could make an argument that navitoclax is one of the better senolytics across the board, but its highly undesirable side-effects make it a poor choice despite its ability to kill a sizable fraction of senescent cells in animal studies. Recent efforts to produce a navitoclax prodrug that only activates in senescent cells, removing those unwanted side-effects, are thus quite exciting.

A surprise here is that metformin turns out to be pretty good at sabotaging the consequences of radiation-induced cellular senescence, presumably by reducing the inflammatory signaling of senescent cells, since it is not a senolytic drug. The researchers treated mice with metformin for 10 weeks, longer than the few doses of the shorter senolytic treatments, which perhaps allowed the immune system to catch up and remove more senescent cells than would otherwise have been the case. For practical outcomes in mouse health following irradiation, such as frailty and organ function, this longer metformin treatment turns out to be about as good as a short dosing period with navitoclax.

Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice

Cancer survivors suffer from progressive frailty, multimorbidity, and premature morbidity. We hypothesize that therapy-induced senescence and senescence progression via bystander effects is a significant cause of this premature ageing phenotype. Accordingly, the study addresses the question whether a short anti-senescence intervention is able to block progression of radiation-induced frailty and disability in a pre-clinical setting. Male mice were sub-lethally irradiated at 5 months of age and treated (or not) with either a senolytic drug (Navitoclax or dasatinib + quercetin) for 10 days or with the senostatic metformin for 10 weeks. Follow up was for one year.

Treatments commencing within a month after irradiation effectively reduced frailty progression and improved muscle and liver function as well as short-term memory until advanced age with no need for repeated interventions. Senolytic interventions that started late, after radiation-induced premature frailty was manifest, still had beneficial effects on frailty and short-term memory. Metformin was similarly effective as senolytics. At therapeutically achievable concentrations metformin acted as a senostatic neither via inhibition of mitochondrial complex I, nor via improvement of mitophagy or mitochondrial function, but by reducing non-mitochondrial ROS production via NOX4 inhibition in senescent cells.

Our study suggests that the progression of adverse long-term health and quality-of-life effects of radiation exposure, as experienced by cancer survivors, might be rescued by short-term adjuvant anti-senescence interventions.

Retinal degeneration is a prevalent issue in later life, and age-related macular degeneration is the poster child for this class of conditions. It is irreversible at present, setting aside a few technology demonstrations of gene therapies and cell therapies, but researchers are seeking cost-effective ways to at least slow it down. Mitochondria are the power plants of the cell, responsible for packaging energy store molecules to power cellular processes. They also generate potentially harmful free radicals while doing so. Mitochondrial function declines with age, less packaging and more free radicals, and this contributes to issues in many tissues, including the retina. A range of present approaches can improve mitochondrial function, such as NAD+ upregulation via vitamin B3 derivatives, or mitochondrially targeted antioxidants, but none of them appear to be any better than exercise. Perhaps the next generation of such technologies will be, but this remains to be seen.

In patients with age-related macular degeneration (AMD), the crucial retinal pigment epithelial (RPE) cells are characterized by mitochondria that are structurally and functionally defective. Moreover, deficient expression of the mRNA-editing enzyme Dicer is noted specifically in these cells. This Dicer deficit up-regulates expression of Alu RNA, which in turn damages mitochondria - inducing the loss of membrane potential, boosting oxidant generation, and causing mitochondrial DNA to translocate to the cytoplasmic region. The cytoplasmic mtDNA, in conjunction with induced oxidative stress, triggers a non-canonical pathway of NLRP3 inflammasome activation, leading to the production of interleukin-18 that acts in an autocrine manner to induce apoptotic death of RPE cells, thereby driving progression of dry AMD.

It is proposed that measures which jointly up-regulate mitophagy and mitochondrial biogenesis (MB), by replacing damaged mitochondria with "healthy" new ones, may lessen the adverse impact of Alu RNA on RPE cells, enabling the prevention or control of dry AMD. An analysis of the molecular biology underlying mitophagy/MB and inflammasome activation suggests that nutraceuticals or drugs that can activate Sirt1, AMPK, Nrf2, and PPARα may be useful in this regard. These include ferulic acid, melatonin, urolithin A, and glucosamine (Sirt1), metformin and berberine (AMPK), lipoic acid and broccoli sprout extract (Nrf2), and fibrate drugs and astaxanthin (PPARα). Hence, nutraceutical regimens providing physiologically meaningful doses of several or all of the above may have potential for control of dry AMD.

Link: https://doi.org/10.3390/nu14091985

This interesting study from earlier this year shows that administration of plasmalogens to old mice produces a sizable reduction in markers of inflammation in the brain, an effect that seems driven by changed behavior of microglia. These innate immune cells are resident in the central nervous system and become overly activated and inflammatory in later life, driving an inflamed environment that degrades tissue function in the brain. Some of this is due to cellular senescence, but not all of it, so while senolytics appear quite effective in animal models of inflammatory neurodegeneration, other approaches will likely also be needed.

Neurodegeneration is a pathological condition in which nervous system or neuron losses its structure, function, or both leading to progressive neural degeneration. Growing evidence strongly suggests that reduction of plasmalogens (Pls), one of the key brain lipids, might be associated with multiple neurodegenerative diseases, including Alzheimer's disease (AD). Plasmalogens are abundant members of ether-phospholipids. Approximately 1 in 5 phospholipids are plasmalogens in human tissue where they are particularly enriched in brain, heart and immune cells.

In this study, we employed a scheme of 2-months Pls intragastric administration to aged female C57BL/6J mice, starting at the age of 16 months old. Noticeably, the aged Pls-fed mice exhibited a better cognitive performance, thicker and glossier body hair in appearance than that of aged control mice. The transmission electron microscopic (TEM) data showed that 2-months Pls supplementation surprisingly alleviates age-associated hippocampal synaptic loss and also promote synaptogenesis and synaptic vesicles formation in aged murine brain. Further analyses confirmed that plasmalogens remarkably enhanced both the synaptic plasticity and neurogenesis in aged murine hippocampus. In addition, we have demonstrated that Pls treatment inhibited the age-related microglia activation and attenuated the neuroinflammation in the murine brain.

These findings suggest for the first time that Pls administration might be a potential intervention strategy for halting neurodegeneration and promoting neuroregeneration.

Link: https://doi.org/10.3389/fmolb.2022.815320

In today's open access paper, researchers review what is known of the ways in which the hallmarks of aging are involved in the aging of the brain, from initial cognitive decline through to later dementia. Interestingly, chronic inflammation is increasingly implicated in brain aging and the onset of dementia, and many of the hallmarks can be connected to inflammation. This is a direct connection in some cases, such as the presence of senescent cells that generate an outsized amount of pro-inflammatory signaling in comparison to their numbers. Other issues produce inflammation more indirectly, such as the numerous impairments in cell function, including disarray in mitochondrial function, autophagy, and epigenetic patterns, that lead to failure of the blood-brain barrier. That barrier leaks, leading to inflammation as inappropriate molecules and cells make their way into the brain.

Epigenetic aging is an increasingly interesting topic, given the prospect of epigenetic rejuvenation via partial reprogramming. Epigenetic changes that occur with aging are perhaps caused by cycles of DNA damage and repair, causing a depletion of factors needed to maintain youthful epigenetics. Reprogramming causes a reset in epigenetic marks, and resulting benefits in cell function. To what degree do age-related epigenetic changes result in inflammatory behavior in addition to other dysfunctions in cell behavior? That is an interesting question that has yet to be usefully answered. As noted above, the consequence of inflammation many not be a direct outcome of changed cell behavior, and rather lie at the end of a chain of downstream items. The best way to find out is for the research community to continue to apply reprogramming therapies in animal studies and observe the outcomes.

Biological aging processes underlying cognitive decline and neurodegenerative disease

Alzheimer's disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. After the age of 65, the incidence of ADRD nearly doubles every 5 years, and by the ninth decade of life, approximately one of every three adults meets criteria for dementia. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms.

Biological pathways underlying normal cognitive aging and ADRD are likely to overlap, existing along a continuum. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. The biology-of-aging field has made substantial gains in identifying the pathophysiological processes that contribute to biological aging and multisystem organ decline.

In a seminal paper, researchers defined nine hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, altered intercellular communication, and cellular senescence. These aging hallmarks and others have been implicated as pathogenic factors underlying numerous chronic age-related diseases, including ADRD. In animal models, targeting biological aging processes has extended both lifespan and healthspan, suggesting the possibility that these approaches may have beneficial effects for cognitive health as well.

NF-κB is a well studied player in the complex regulatory systems that control the production and processing of inflammatory signaling in cells. Cells sense their environment and produce inflammatory signals in reaction to prompts, drawing in immune cells to investigate and amplify the local response if necessary. Unfortunately the cell and tissue damage characteristic of aging triggers cells into producing inflammatory signals. The consequent chronic inflammation is disruptive of tissue function throughout the body, contributing to degenerative aging. Sophisticated control over inflammatory signaling, eliminating excess inflammation while allowing necessary inflammatory signaling to proceed, is thus an important goal in the treatment of aging.

It is important to identify connections between seemingly unrelated mechanisms of ageing, or to discover new aspects of ageing biology. One of the master transcriptional regulators at the crossroads of immunity and ageing is nuclear factor kappa B (NF-κB), with its diverse roles implicated in nearly all the hallmarks of ageing. In this mini review, we aim to expose relatively unexplored topics surrounding NF-κB in the spirit of 'leave no stone unturned'. In both the innate and the adaptive immune systems, NF-κB senses danger signals and regulates the expression of cytokines and their receptors in a complex cell-cell communication cascade. Therefore, any age-related intrinsic defects of NF-κB signaling would have a direct impact on cell-cell communications within the immune system and with the surrounding microenvironments.

Here we discuss evidence and ideas for the relevance of NF-κB in two concepts of immune ageing: inflammageing and declining adaptive immunity (immunosenescence). Activated in virtually all cell-cell communication networks of the immune system, NF-κB is thought to affect age-related defects of both innate and adaptive immune cells, relevant to inflammageing and declining adaptive immunity, respectively. Moreover, the family of NF-κB proteins that exist as heterodimers and homodimers exert their function beyond the immune system. Given their involvement in diverse areas such as DNA damage to metabolism, NF-κB has the potential to serve as linkages between known hallmarks of ageing. However, the complexity of NF-κB dimer composition, dynamic signaling, and tissue-specific actions has received relatively little attention in ageing research.

Link: https://doi.org/10.1186/s12979-022-00277-w

The Lifespan.io team here talks with one of the co-founders of Turn.bio, one of the first biotech ventures focused on partial reprogramming as a basis for rejuvenation therapies. Their initial technology involves the delivery of lipid nanoparticles that encapsulate mRNA for temporary expression of the Yamanaka factors. Full reprogramming dedifferentiates and rejuvenates cells, turning somatic cells into induced pluripotent stem cells with youthful epigenetic patterns. Epigenetic rejuvenation is desirable, but producing pluripotent cells in the body is not. Partial reprogramming attempts to apply reprogramming factors for long enough to reset epigenetic patterns to a youthful level, but not for so long as to cause cells to change their state. Looking at the field as a whole, the major thrust of present research and development efforts might be viewed as the search for a reliable way to separate dedifferentiation from epigenetic rejuvenation.

We have seen very significant progress during the last two, three years. Back in 2019, many people still thought that this idea of transient cellular reprogramming, or partial reprogramming, was more science fiction than science. Today, mainstream science, researchers, companies around the world are trying to find the best way to rejuvenate cells. Many labs have started working on these ideas since we published our work. I strongly believe that our proprietary approach, which we call ERA (Epigenetic Reprogramming of Aging), holds the greatest promise in regenerative medicine, because it's a finely tuned and controlled way to reset the epigenetic landscape of cells to a more youthful, functional phenotype without impacting their identity, which is obviously a risk factor that's associated with reprogramming.

We will be moving to human trials very soon, hopefully. We're progressing very rapidly on a couple of indications in dermatology and immunotherapy. Soon, we're going to move into at least Phase I clinical trials. I always like to emphasize the fact that Turn as a company is not just about ERA. This is the foundational technology of Turn, but at the same time, since it relies on the delivery of mRNAs that are used to perform that resetting of the epigenetic landscape, we are also working heavily on the cargo (that is, the mRNAs), and on the delivery system. These three are the three pillars of Turn that are going to enable rapid clinical implementation of this technology for a variety of indications. There has been great progress in terms of research on all three of those, but most importantly, there has been major progress recently in partnering up with big players in the pharma field that are mission oriented.

Link: https://www.lifespan.io/news/reprogramming-cells-with-vittorio-sebastiano-of-turn-bio/

Many forms of mild, intermittent stress produce an overall net benefit to cell and tissue function: low nutrient intake; heat; cold; excessive oxidative molecules; some toxins; and the topic of today's open access paper, hypoxia. When under stress, cells react with increased maintenance efforts aimed at removing damaged molecules and structures. If the stress is mild or of short duration, then the damage done it outweighed by the ongoing repair carried out. Work on the biochemistry of the beneficial response to calorie restriction suggests that autophagy is the most important of these processes, but there are others. In autophagy, molecules and structures are engulfed in an autophagosome and moved to a lysosome where they are broken down for recycling.

In the research noted here, scientists apply an intermittent hypoxia treatment to older patients for half a year and see a modest improvement in only some measures of metabolic health. Chronic inflammation and fat mass were reduced, though the effect size compares unfavorably with structured exercise programs, as is near always the case in these efforts to upregulate cellular maintenance processes. Additionally, a range of other health parameters remained unchanged, an outcome that definitely compares unfavorably with exercise, which tends to produce benefits across the board.

Intermittent Hypoxia as a Therapeutic Tool to Improve Health Parameters in Older Adults

Oxygen is essential for human life, playing a determining role in aerobic respiration and cellular metabolism. A decrease in oxygen (hypoxia) could be deleterious for cellular adaptation and survival. In addition, sustained hypoxia contributes to functional decline during the aging process. Chronic exposure to severe hypoxia leads to an increased oxidative stress, vasoconstrictor activation, systemic inflammation, hypoxemia, pulmonary hypertension, and myocardial ischemia. Conversely, intermittent exposures to moderate hypoxia could have beneficial health effects in both healthy and diseased individuals.

Intermittent hypoxia (IH), defined as short alternating exposures to hypoxia and normoxia, can change body composition and health status with improved exercise tolerance, metabolism, and systemic arterial pressure. It has also been presented as a promising tool to beneficially impact bone metabolism. IH exposure allows modulating and stabilizing the hypoxia-inducible factor-1 alpha (HIF-1α), which is involved in the expression of factors related to angiogenesis, osteogenesis, lipolysis, and regulation of the inflammatory response.

Previous studies have suggested that IH could positively influence age-related alterations in older adults. The aim of this study was to evaluate the effect of 24 weeks of moderate intermittent hypoxia exposure on parameters related to body composition, inflammation, cardiovascular, and bone health in older adults. We hypothesized that IH intervention will have a positive effect on these health parameters. A total of 38 healthy older adults (aged 65-75 years) were divided into two groups: control group (C), and hypoxia group (H) that was subjected to an intermittent hypoxia exposure (at simulated altitude of 2500 m above sea level) during a 24-week period (3 days/week).

The results obtained have shown that IH exposure leads to beneficial effects on the health of the older adults. However, our initial hypothesis has only been partially fulfilled. After 24 weeks of intervention with IH, there has been a decrease in fat mass and C-reactive protein concentrations, as well as an improvement in blood biomarkers of bone remodeling, but no significant changes have been observed in bone mineral content and bone mineral density, nor in the metabolic and cardiovascular health parameters.

The Lifespan.io team here notes a recent study in which researchers carefully induced greater expression of FOXM1 in aged mice, showing extension of life as a result. FOXM1 overexpression is known to induce greater stem cell activity, but also to push somatic cells towards a more cancer-like phenotype, meaning more growth, more regeneration, more activity. Cancer and regeneration are two sides of the same coin. Regeneration and tissue maintenance are controlled processes, while a cancer is driven by the same mechanisms when they run wild.

Given these connections, it is not too surprising to find that FOXM1 is downregulated in older individuals, perhaps a part of the general decline in stem cell function, regeneration, and growth that is characteristic of aging. There is a trade-off in later life between tissue maintenance and risk of cancer, due to rising levels of molecular damage, and evolution has selected for a slow decline rather than a longer period of vitality with greater risk of sudden death by cancer. As the successes of stem cell treatments and various other pro-regenerative approaches to therapy make clear, it is nonetheless possible to push the body towards greater tissue maintenance without causing a greatly increased risk of cancer.

Forkhead box (FOX) genes are transcription factors: genes that drive the expression of other genes and are known to play an important role in cell proliferation and longevity. FOXM1 is another forkhead box gene that has gained the attention of aging researchers as an important oxidative stress response regulator and one of the major players in tumorigenesis. Previous studies have shown that FOXM1 is decreased in the cells of older healthy people as well as people whose aging is accelerated by Hutchinson-Gilford progeria syndrome.

In this study, the researchers set out to check if it's possible to delay aging by increasing the expression of FOXM1 in progeroid and naturally aged mice. However, instead of inducing the fully functioning FOXM1, a modified gene that did not contain an N-terminal part was chosen. The C-terminal side of FOXM1 plays an important role in transcriptional activity, and the N-terminal side plays a role in the regulation of intracellular processes, such as controlling the segregation of genetic material during cell division. The N-terminal side was also shown to have an autoinhibitory function repressing the activity of the protein at specific cell cycle stages.

Although promising, the results from experiments in progeroid mice might not translate into naturally aging animals. Therefore, the researchers applied truncated FOXM1, using a 3-day-on and 4-day-off scheme, for 80 weeks to 8-week-old naturally aging mice. Remarkably, the treatment extended the lifespan of aged mice by almost 30% compared to controls. Tissue examination revealed that truncated FOXM1 induction rejuvenated multiple organs: aorta, skin, fat, and muscle. The researchers observed reduced muscle atrophy and a higher number of muscle stem cells, along with increased muscle strength. In addition, decreased aortic fibrosis and wall thickening, as well as increased subcutaneous fat, were demonstrated. Confirming previous results, naturally aging mice had downregulated senescence biomarkers in skin, kidney, fat, and muscle following truncated FOXM1 induction.

Link: https://www.lifespan.io/news/foxm1-induction-extends-lifespan-in-mice/

Researchers here implicate an age-related reduction in Tom70 levels in the decline in mitochondrial function that takes place in later life. Mitochondria are the power plants of the cell; when their production of the chemical energy store molecule ATP is diminished, then all cell functions suffer as a result. Mitochondrial dysfunction with age is thought to produce a significant contribution to degenerative aging, and a broad range of research and development efforts are devoted to finding ways to address this problem. Research into Tom70 is at a very early stage, so it remains to be seen as to how useful this discovery will be. It seems likely, at the present time, based on what is known now, that the most important approaches to mitochondrial aging will be (a) epigenetic reprogramming to restore youthful expression of relevant proteins and (b) replacement of a patient's mitochondria via intravenous delivery of large numbers of mitochondria manufactured in cell cultures, to be taken up by cells and put to work.

Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins.

Here, we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription, biogenesis, and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mitochondrial DNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan in budding yeast. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.

Link: https://doi.org/10.7554/eLife.75658

All cancerous cells must lengthen their telomeres in order to continue unfettered, harmful replication. Telomeres are repeated DNA sequences at the ends of chromosomes. A little telomere length is lost with each cell division, and cells with short telomeres following repeated replication become senescent or self-destruct. This is how the Hayflick limit on somatic cell replication is enforced. Unlike somatic cells, stem cells are privileged, and use telomerase to lengthen telomeres in order to produce daughter somatic cells via replication throughout life. Cancer cells, on the other hand, use either telomerase (~90% of cancers) or a partially explored set of mechanisms called alternative lengthening of telomeres (ALT, ~10% of cancers).

In this context, I'll mention what I think to be a good idea for a new biotech venture, suitable for someone who likes to take on a little more risk at the outset. Set forth to conduct a program of screening for small molecules that interfere in ALT. The aim is to discover compounds that can be used to treat the 10% of cancers that employ ALT, shutting down their ability to replicate. This is a somewhat open part of the field, as little funding goes towards such pure, focused discovery efforts in comparison to the funding for groups that already have an identified small molecule. Yet it is a reasonable wager that a large enough screening effort will turn up something useful along the way.

ALT is an attractive target for drug development. It only operates in cancerous cells, not normal cells, so there are fewer concerns regarding off-target effects. Interfering in ALT is a necessary part of a future universal cancer therapy that comprehensively prevents telomere lengthening. This is the best and most fundamental way to eliminate cancer, an approach that cancers can neither evade nor evolve resistance to. Even 10% of cancers is a vast market for one drug. The SENS Research Foundation tried a modestly sized screening program a few years ago, and didn't find good targets. Since then the research community has uncovered new information that might lead to a more guided screening process, such as the roles of FANCM and TRIM28. It is worth a try!

Alternative Lengthening of Telomeres and Mediated Telomere Synthesis

Telomeres are located at the end of eukaryotic chromosomes, and in humans, they are composed of TTAGGG tandem repeat DNA sequences and telomere-binding proteins. They are special structures that do not carry genetic information, and they comprise a proximal double-stranded region and the distal single-stranded region. Telomeres prevent the loss of genetic information during DNA replication and protect chromosomes from end fusion. Except in embryonic germ cells, stem cells, and cancer cells, telomere length gradually shortens with cell division. Short or dysfunctional telomeres are recognized as double-strand breaks (DSBs), triggering replicative senescence of cells.

Telomere maintenance is essential for genomic stability and survival of proliferating cells. To escape from the "Hayflick limit", the majority of tumor cells reactivate telomerase, which maintains telomere length. Telomerase maintains telomere length by adding telomere DNA repeats to the end of telomeres. This enzyme consists of a protein component with reverse transcriptase activity and an RNA component that is the template for telomeric DNA synthesis. However, approximately 10 to 15% of human tumors preferentially maintain telomeres through the alternative lengthening of telomeres (ALT) pathway, which is a potential therapeutic target for telomerase-negative tumors.

The ALT phenotype has been observed in a broad range of human cancers, and some ALT-related cancers are aggressive. However, the development of anti-cancer therapeutics targeting the ALT pathway has been greatly limited by a failure to understand the molecular mechanisms underlying ALT pathway action and initiation. Here, we review recent discoveries regarding the ALT pathway mechanism and discuss possible cancer therapy targets in the ALT pathway.

Why is degenerative aging near universal in the animal kingdom? The present consensus explanation is that natural selection acts most strongly on early reproductive life, selecting for mechanisms that are beneficial at the outset of life, heedless of later life harms when those mechanisms run awry over time. Yet why is it the case that so many of the mechanisms beneficial in young animals are also harmful in older animals? Why is this inevitable? Here it is argued that this is an outcome of the highly interconnected nature of cellular biochemistry. Every protein has many functions and influences the function of many other proteins. It is near impossible to change anything in a cell without impacting many related processes in some way; any change will have many distinct consequences, some of which will be detrimental.

Aging rate differs greatly between species, indicating that the process of senescence is largely genetically determined. Senescence evolves in part due to antagonistic pleiotropy (AP), where selection favors gene variants that increase fitness earlier in life but promote pathology later. Identifying the biological mechanisms by which AP causes senescence is key to understanding the endogenous causes of aging and its attendant diseases. Here we argue that the frequent occurrence of AP as a property of genes reflects the presence of constraint in the biological systems that they specify.

The claim that AP is important in the evolution of aging implies that many genes must exhibit AP. But why should so many genes have this property? The likely answer here lies in the existence of a high degree of biological constraint, arising from the highly integrated nature of biological systems. As Stephen Jay Gould put it, when discussing the evolution of anatomy: "any adaptive change in a complex and integrated organism must engender an automatic (and often substantial) set of architectural byproducts".

This means that a new allele that alters one trait in a way that enhances fitness can easily affect other traits adversely. To use a simple example: for fundamental thermodynamic reasons increasing ATP production rate reduces ATP yield and vice versa. Therefore a mutation increasing ATP production rate will exhibit AP and reduce ATP yield; here ATP yield is traded off against production rate. This illustrates how AP can arise not only from properties of the molecular biology of genes or their RNA or protein products, which tend to be the focus of accounts of pleiotropy, but also from properties of the systems that those products impact.

Link: https://doi.org/10.20944/preprints202205.0212.v1

It is reasonable to think that interventions successfully targeting one or more mechanisms of aging will produce benefits across all higher animals. The underlying mechanisms of aging are quite universal. Equally, it is reasonable to think that different species are impacted to different degrees by any given mechanism of aging, and thus interventions may produce small or sizable benefits, depending on the details. Researchers here comment on the ability to produce cross-species epigenetic clocks, in that there are patterns of epigenetic marks on equivalent sites in the genome in two or more species that correlate to chronological age in the same way. Does this then imply that a therapy that both reverses this pattern and extends healthy life span in one species can be expected to do the same in the other? Perhaps, but I don't think that to be a sure bet.

DNA methylation profiles have been used to develop biomarkers of aging known as epigenetic clocks, which predict chronological age with remarkable accuracy and show promise for inferring health status as an indicator of biological age. Epigenetic clocks were first built to monitor human aging, but their underlying principles appear to be evolutionarily conserved, as they have now been successfully developed for many mammalian species.

Here, we describe reliable and highly accurate epigenetic clocks shown to apply to 93 domestic dog breeds. The methylation profiles were generated using the mammalian methylation array, which utilizes DNA sequences that are conserved across all mammalian species. Canine epigenetic clocks were constructed to estimate age and also average time to death.

We also present two highly accurate human-dog dual species epigenetic clocks, which may facilitate the ready translation from canine to human use (or vice versa) of antiaging treatments being developed for longevity and preventive medicine. These clocks, which measure methylation levels in highly conserved stretches of the DNA, promise to increase the likelihood that interventions that reverse epigenetic age in one species will have the same effect in the other.

Link: https://doi.org/10.1073/pnas.2120887119

Urolithin A is one of a number of supplements under assessment for their ability to improve mitochondrial function in older adults. Mitochondria are the power plants of the cell, producing chemical energy store molecules vital to all cellular processes. Improved mitochondrial function should result in improved tissue function throughout the body, such as in skeletal muscle, a tissue with high energy requirements. You might recall the results published from a small human study earlier this year. Some measures of strength and endurance were improved, but as is the case for other, similar approaches to reducing age-related mitochondrial dysfunction, the gains are not as large as those that can be obtained via structured exercise programs. It is questionable as to whether significant time and funding should be devoted to these approaches.

Mitochondrial function declines with age, and evidence to date suggests that loss of efficacy in mitophagy is an important part of this aspect of degenerative aging. Mitophagy is a complex process of many stages in which damaged and worn mitochondria are identified, transported to a lysosome, and broken down. Defects in any part of this process, such as a reduced expression of critical proteins due to age-related changes in epigenetic regulation, will reduce overall efficiency of mitophagy. When mitophagy falters, dysfunctional mitochondria accumulate to the detriment of the cell. Urolithin A is thought to produce its benefits to mitochondrial function by restoring greater efficiency in mitophagy, though exactly how this is achieved is up for debate.

Clinical study shows postbiotic urolithin a improves muscle strength and exercise performance in middle aged adults

A new study shows that daily intake of Urolithin A significantly improved muscle strength by 12% after four months. This works by supporting the cells' ability to renew their power plants, the mitochondria, during the aging process. Muscles have a high demand for energy and there are a very large number of mitochondria in muscle cells.

Two measures of skeletal muscle strength were improved in the supplemented groups compared to the placebo group. Muscle strength in the hamstring skeletal muscle was significantly increased in both 500mg (+12%) and 1,000mg groups (+9.8%). Muscle strength during knee flexion was also significantly improved at both 500mg (+10.6%) and 1,000mg doses (+10.5%). The blood tests and biopsies showed a significant improvement in biomarkers of healthy mitochondrial function and reduced inflammation.

Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults

Targeting mitophagy to activate the recycling of faulty mitochondria during aging is a strategy to mitigate muscle decline. We present results from a randomized, placebo-controlled trial in middle-aged adults where we administer a postbiotic compound Urolithin A, a known mitophagy activator, at two doses for 4 months (NCT03464500). The data show significant improvements in muscle strength (∼12%) with intake of Urolithin A. We observe clinically meaningful improvements with Urolithin A on aerobic endurance (peak oxygen oxygen consumption [VO2]) and physical performance (6 min walk test) but do not notice a significant improvement on peak power output (primary endpoint).

Levels of plasma acylcarnitines and C-reactive proteins are significantly lower with Urolithin A, indicating higher mitochondrial efficiency and reduced inflammation. We also examine expression of proteins linked to mitophagy and mitochondrial metabolism in skeletal muscle and find a significant increase with Urolithin A administration.

Researchers have in the past shown that exercise results in greater amounts of BDNF, which in turn promotes neurogenesis. Here, this line of research is extended to show that exercise results in an increased release of dopamine, and this benefit depends on BDNF upregulation. Dopamine is important in brain function, but the loss of dopamine that takes place in Parkinson's disease, as dopamine-secreting cells are destroyed, is most likely the primary motivation for this study.

Experts have long understood that regular running raises dopamine activity in the brain and may protect nerve cells from damage. In addition, past research has tied exercise-driven boosts in the dopamine-triggering chemical called brain-derived neurotrophic factor (BDNF) and in dopamine levels to improvements in learning and memory. However, the precise way these three factors interact has until now remained unclear.

A new study showed that mice running on a wheel for 30 days had a 40 percent increase in dopamine release in the dorsal stratium, the part of the brain involved in movement, compared to levels in mice that did not exercise. The runners also showed a nearly 60 percent increase in BDNF levels compared to their non-running counterparts. Notably, the increase in dopamine release remained elevated even after a week of rest. Additionally, when BDNF levels were artificially reduced, running did not lead to additional dopamine release.

For the investigation, researchers provided dozens of male mice with unlimited access to either a freely rotating wheel or a locked wheel that could not move. After one month, the team measured dopamine release and BDNF levels in brain slices. They repeated this same process on a new group of rodents, some of which had been genetically modified to produce half as much BDNF as regular mice. "Our results help us understand why exercise alleviates the symptoms of Parkinson's disease, as well as those of neuropsychiatric disorders such as depression. Now that we know why physical activity helps, we can explore it as a means of augmenting or even replacing the use of dopamine-enhancing drugs in these patients."

Link: https://nyulangone.org/news/boost-nerve-growth-protein-helps-explain-why-running-supports-brain-health

Senescent cells accumulate with age and produce tissue dysfunction through their pro-growth, pro-inflammatory signaling. Here researchers report on an example of fisetin supplementation reducing the burden of senescent cells in the vasculature of old mice. It also improves other measures of tissue health. The dose used here is not as high as that in the first mouse study to show fisetin clearing senescent cells, but the dosing schedule is longer.

There remains some question as to whether fisetin at suitably high doses will in fact prove to be usefully senolytic in humans, capable of clearing senescent cells to the same degree as in mice. Currently the dasatinib and quercetin combination is the only senolytic with solid human data to show that it works as well in our species as it does in mice. Questions about fisetin will hopefully be answered by the publication of results from ongoing clinical trials sometime in the next few years. If it does turn out to be as good in humans as it is in mice, that will be of great benefit to health in later life.

Age-related vascular endothelial dysfunction is mediated by excess reactive oxygen species (ROS) - mitochondria being a key source - which can reduce nitric oxide (NO) bioavailability. Cellular senescence, a fundamental mechanism of aging, may exacerbate mitochondrial ROS and be a potential therapeutic target to combat age-related vascular dysfunction. This study ran to determine if treatment with the natural flavonoid fisetin improves endothelial function with aging by suppressing cellular senescence, scavenging excess whole-cell and mitochondrial ROS, and increasing NO bioavailability.

Old (27 mo) male C57BL/6 mice were treated with fisetin (50 mg/kg/day) by oral gavage following a 1 week on - 2 week off - 1 week on dosing paradigm. Endothelial function was assessed by ex vivo carotid artery endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) to increasing doses of acetylcholine and sodium nitroprusside, respectively. Electron paramagnetic resonance (EPR) spectroscopy was used to assess vascular mitochondrial ROS.

EDD was greater in fisetin versus control mice (Peak EDD [%]: 97 ± 1 vs 84 ± 3). Fisetin-treated mice had lower vascular abundance of p16, an established marker of cellular senescence (.12 ± .01 vs .19 ± .02 chemiluminescence units). Fisetin-treated mice had lower mitochondrial ROS (2527 ±440 vs 6603 ± 1956 AU). Further, Fisestin-treated mice had lower abundance of vascular p-p66SHC, a recognized marker of mitochondrial oxidative stress (.029 ± .003 vs .049 ± .008 CU) and greater abundance of Mn superoxide dismutase, a mitochondrial antioxidant enzyme (.41 ± .1 vs .20 ± .02 CU).

In conclusion, fisetin supplementation may be a novel strategy to target excess cellular senescence and thereby reduce mitochondrial ROS to improve NO-mediated endothelial function with aging.

Link: https://doi.org/10.1096/fasebj.2022.36.S1.R1931

If decent odds of living into late old age are the desired goal, in the present medical environment in which the easily available, widely used technologies still have comparatively little impact on aging and age-related disease, then good lifestyle choices are paramount. Don't smoke. Stay thin. Eat a good diet. That lifestyle choices have a sizable impact on aging in comparison to available medical technologies is a sign that the research and development communities are not yet very far along in the treatment of aging. We might hope that this will change in the years ahead, starting with the widespread use of first generation senolytic therapies to remove senescent cells and the harms that they cause.

How large an effect on life expectancy results from good versus bad lifestyle choices? Epidemiological studies such as that noted in today's open access paper can be used to answer this question. People making poor lifestyle choices had a 28% chance of reaching age 85, while people making better lifestyle choices had a 67% chance of reaching age 85. While no-one gets to be 85 with a youthful physique, at least not until rejuvenation therapies are a lot further along, there is something to be said for being alive versus the alternative, particularly as progress in medical technology will continue along the way, offering better options as time goes on.

Healthy Choices in Midlife Predict Survival to Age 85 in Women: The Tromsø Study 1979-2019

The aim of this study is to examine the association between single risk factors and multiple risk factors in midlife and older ages (up to 64 years) and survival to the age of 85 years in women. The study sample comprised 857 women who attended the second survey of the population-based Tromsø Study (Tromsø2, 1979-1980) at the ages of 45-49 years and were followed for all-cause mortality until 85 years of age. Daily smoking, physical inactivity, being unmarried, obesity, high blood pressure, and high cholesterol in midlife were used as explanatory variables in survival analyses.

In total, 56% of the women reached the age of 85. Daily smoking, physical inactivity, being unmarried, and obesity were significant single risk factors for death before the age of 85. None of the women had all six risk factors, but survival to age 85 did decrease gradually with increasing number of risk factors: from 67% survival for those with no risk factors to 28% survival for those with four or five risk factors. A subset of the study sample also attended the third and fourth surveys of the Tromsø Study (Tromsø3, 1986-1987 and Tromsø4, 1994-1995, respectively).

Women who quit smoking and those who became physically active between Tromsø3 and Tromsø4 had higher survival when compared to those who continued to smoke and remained physically inactive, respectively. This study demonstrates the importance of having no or few risk factors in midlife with respect to longevity. We observed a substantial increase in the risk of death before the age of 85 among women who were daily smokers, physically inactive, unmarried, or obese in midlife. This risk may be mitigated by lifestyle changes, such as quitting smoking and becoming physically active later in life.

Cellular reprogramming is a hot topic these days, given the vast amount of funding devoted to research and development, and the number of well capitalized new ventures focused on building therapies based on reprogramming. Reprogramming recaptures the process that takes place in the early embryo in which cells become pluripotent, but also reset their epigenetic patterns to restore mitochondrial function and other cellular processes to a youthful configuration. The primary goal of most reprogramming initiatives is to avoid pluripotency and state change in cells, while still restoring youthful epigenetic control of gene expression and cell function - a work in progress, moving ahead with enthusiasm. That said, there are a range of issues that this approach cannot address well, from nuclear DNA damage to persistent molecular waste, but it seems plausible that useful rejuvenation therapies will result from this line of work.

We are trying to translate partial cellular programming, but we have a tight focus right now on humans. Our approach is to use gene therapy to deliver reprogramming genes once into tissues of interest and then activate them with a small molecule. Ultimately, we feel that partial cellular reprogramming will need a tissue-specific approach. Different organs will probably need different reprogramming factors and definitely different dosing regimens.

Our goal is to create tissue-specific gene induction systems that, for a given tissue, can activate a specific set of genes. That platform doesn't even have to be used for partial cellular programming. It could potentially be used for any other gene therapy that needs several different gene cargoes that need to be activated in a different manner.

Eventually, we also want to move away from Yamanaka factors, because they weren't designed for partial programming. They were designed for full reprogramming, and for our purposes are too dangerous, because full reprogramming causes cells to lose their identity. This is something we obviously do not want, so we're looking for other factors that are better suited to partial reprogramming. Basically, the holy grail for us is to split the rejuvenation from the dedifferentiation. We want to just rejuvenate cells if it's possible.

To me, the beauty of partial cellular reprogramming is actually that it doesn't really matter what aging is. We're taking a very pragmatic approach. We absolutely know that a lot of epigenetic changes are driving aging. Do those changes happen in response to stochastic damage? Or because of a program? For practical purposes it doesn't really matter. We have observations that show that partial cellular reprogramming can delay aging and can reverse some hallmarks of aging on the cellular level. We also see some reversal of those hallmarks on an organ level and potentially on a systemic level. There is definitely a delay of aging in the progeric mouse model where they lived up to 50% longer and exhibited better histology of various tissues.

We are taking a pragmatic approach to translating this research to people. We're actually trying to make something useful rather than just taking a dive deep into the fundamental science, which of course is also important and interesting, but we ultimately want to create a therapy for people as quickly as possible.

Link: https://www.lifespan.io/news/yuri-deigin-on-cellular-reprogramming-in-humans/

Researchers here discuss evidence for the involvement of the nervous system in the progression of atherosclerosis, the formation of ultimately fatal fatty deposits in blood vessel walls. These atherosclerotic lesions are sites of inflammation, drawing in macrophage cells of the innate immune system that attempt to repair the injury, but become overwhelmed by cholesterol, die, and add their mass to the growing plaque. It also appears that the presence of atherosclerotic plaque activates signals that pass via the nervous system to the brain and then to the spleen. In the spleen, monocyte cells held in reserve are activated, enter the bloodstream, travel to the plaque to become macrophages, and thus make matters worse. Atherosclerosis is a good example of a normally beneficial repair system in the body, the delivery of macrophages to injuries, becoming pathological in later life, causing harm rather than helping.

New research demonstrates for the first time the existence of a connection between atherosclerotic plaques and the central nervous system, which in turn, through the spleen, it activates the immune system, further stimulating the development of the disease. This hitherto unknown "nervous circuit" could represent a target for innovative therapies.

In correspondence with an atherosclerotic plaque an aggregate of immune cells is also formed in the external wall of the blood vessel. This aggregate, called an artery tertiary lymphoid organ (ATLO) and similar to a lymph node, is rich in nerve fibers. This work has shown that through them a direct connection is established between the plaque and the brain. "We were able to see that these signals coming from the plaque, once they reach the brain, influence the autonomic nervous system through the vagus nerve until it reaches the spleen. Here there is an activation of specific cells of the immune system that enter the circulation and lead to the progression of the plaques themselves."

It is a real nervous circuit, which the authors of the research have defined as "ABC" or "artery-brain circuit". And like all circuits, it can be disconnected or modulated. "We have conducted further experiments by interrupting the nerve connections that reach the spleen. In this way, the impulses on the immune cells present in this organ have failed. The result is that the plaques present in the arteries have not only slowed growth, but have stabilized."

Link: https://www.neuromed.it/ricerca-le-placche-aterosclerotiche-dialogano-con-il-cervello/

The safe approach to develop treatments for aging is to find natural compounds and existing small molecule drugs with known safety profiles that can adjust metabolism to modestly slow aging. It doesn't aggravate those people with a conservative mindset who fear all change, even beneficial change. It is likely to be successful enough during clinical development to attract funding and give early investors a return on their investment. It is only an incremental step beyond present drug development processes, nothing radical that is likely to raise eyebrows. Thus much of the present longevity industry follows the incentives and takes the easier route.

Unfortunately, near everything derived from this philosophy of development will do very little for human life span. This end of the longevity industry will become just another arm of medical research and development that produces marginal therapies, most of which will fail in later clinical trials because the effect sizes are too small. Why is this the case? It is because researchers screen and test potential treatments in lower species, from yeast to nematode worms to mice, all of which have a much greater plasticity of life span in response to interventions that mimic the response to calorie restriction than is the case for longer-lived species such as our own. Thus most discoveries made in any unbiased search will be compounds that mimic the response to calorie restriction.

This mimicking typically means an upregulation of cellular housekeeping mechanisms such as autophagy. There is plenty of human data to show that calorie restriction, and thus the full panoply of such increased cellular maintenance, is beneficial to health. Calorie restriction doesn't, however, greatly extend life span in long-lived species such as our own: it would have been well known thousands of years ago were this the case. We can't add decades to healthy longevity via stress response upregulation of this sort.

This said, the approach of screening for novel compounds can in principle produce varieties of rejuvenation therapy that result in large improvements in late life health - such as senolytic compounds that selectively kill senescent cells. The development of senolytic therapies is a big win, and will be profoundly influential on human health once the existing low cost senolytics obtain solid clinical trial data and have percolated into common use. But this isn't the median outcome, and a discovery process that is more directed than screening for slowing of aging in mice or nematode worms is needed if we are to live meaningfully longer than our grandparents.

Antiaging agents: safe interventions to slow aging and healthy life span extension

Over the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries.

Performing clinical trials to study the anti-aging potential of conventional drugs is undoubtedly a very difficult task. This is because older patients often suffer from multiple diseases and receive multiple medications simultaneously. The presence of drug-drug interactions and identified comorbidities make the evaluation of such drugs difficult, especially to assess the full range of effects produced by these drugs, whether beneficial or harmful. The lack of reliable and detectable biomarkers to assess the effectiveness of anti-aging interventions is another serious challenge.

The criteria for a potential anti-aging drug are: (1) a drug that extends the lifespan of a model organism, preferably a mammal; (2) a drug that delays or prevents some aging-related diseases in mammals; and (3) a drug that inhibits the senescence transition of cells from quiescence to senescence. The criteria may overlap. If an intervention is intended to extend lifespan, it must retard diseases associated with aging.

Many plants and fungi contain natural anti-aging products that can extend the lifespan of model organisms. These active molecules regulate the same cellular and physiological pathways that are affected by calorie restriction (CR) and exercise. Compounds that increase lifespan and healthspan mimic the effects of CR, typically by reducing insulin/IGF-1 signaling and activating autophagy and other cellular processes that increase resistance to stress.

Various strategies exist for using the anti-aging agents described here, including dietary supplements, increasing the intake of foods containing large amounts of these molecules, and/or consuming probiotics and prebiotics that raise blood levels of these molecules. Several nutrients and natural compounds have been observed to be related to increased lifespan in humans, suggesting that such strategies are feasible for slowing aging and increasing health span. Plant and fungal molecules with anti-aging properties in model organisms may also lead to the discovery and identification of new bioactive compounds for the development of improved CR mimetics to slow human aging. Except for mentioned above natural products, many other compounds have been reported to show anti-aging activity, such as acetic acid, allicin, apigenin, aspalathin, berberine, capsaicin, catalpol, celastrol, garcinol, huperzine, hydroxycitrate, inositol, naringin, piceatannol, and piperlongumine.

Biogerontology is entering a period of exciting and rapid development. It has great potential for future pharmacological interventions to slow aging. As a new era of anti-aging drug discovery dawns, the research community will need to pay special attention to the timely development of drugs that can slow the aging process, either alone or as multiple agents. Natural products provide the driving force to move forward in our quest to understand and improve the health span, just as they have always done! In regulating aging, it is hoped that these drugs will also reduce the burden of many age-related diseases.

Researchers here report on an analysis of changes in the gut microbiome with age, looking at normally aged mice alongside those undergoing heterochronic parabiosis, probiotic treatment, and injection with serum from young mice. All of the interventions improved the state of the aged gut microbiome and reduced inflammation, but only some produced meaningful changes age-related frailty. The microbial populations of the gut undergo shifts with age, reductions in beneficial species and a growth in harmful species that provoke inflammation. Any intervention that improves immune function should help, given the role of the immune system in gardening the gut microbiome, as do interventions that directly change the balance of populations. In humans, the most promising approach is fecal microbiota transplantation, given that it is already an established procedure, but that doesn't stop researchers from assessing all sort of other interventions in animal studies.

The gut microbiota is associated with the health and longevity of the host. Through the aging process, age-related changes in the composition of gut microbiota have been observed, which are related to increased intestinal disorders, inflammation, cognitive decline, and increased frailty. Furthermore, remodeling of the gut microbiome has resulted in a prolonged lifespan in Drosophila melanogaster, killifish, and progeroid mice. Previous studies have clearly shown that delivery of a healthy microbiome through co-housing or fecal microbiota transplantation (FMT) enhances intestinal immunity and facilitates healthy aging.

The changes in host microbiomes still remain poorly understood. Here, we characterized both the changes in gut microbial communities and their functional potential derived from colon samples in mouse models during aging. We achieved this through four procedures including co-housing, serum injection, parabiosis, and oral administration of Akkermansia muciniphila as probiotics using bacterial 16 S rRNA sequencing and shotgun metagenomic sequencing.

These rejuvenation procedures restore age-dependent alterations in intestinal function and inflammation. Furthermore, oral administration of Akkermansia led to an improvement in the frailty index. The generated data expand the resources of the gut microbiome related to aging and rejuvenation and provide a useful dataset for research on developing therapeutic strategies to achieve healthy active aging.

Link: https://doi.org/10.1038/s41597-022-01308-3

There is some interest in the research community in identifying the specific triggers by which lowered intake of protein leads to beneficial shifts in metabolism and modestly slowed aging. Scientists have shown that reducing only protein intake (such as via reduced intake of methionine, an essential amino acid required for all protein synthesis) while retaining the same level of dietary calories can have similar effects to the practice of calorie restriction, an overall reduction in food intake. Thus methionine sensing is important. It isn't the only mechanism relevant to the benefits to health that result from a lower intake of macronutrients, however. Here, researchers focus on the role of branched-chain amino acids in this context, putting forward the case for branched-chain amino acid sensing to also be an important factor.

The proportion of humans suffering from age-related diseases is increasing around the world, and creative solutions are needed to promote healthy longevity. Recent work has clearly shown that a calorie is not just a calorie - and that low protein diets are associated with reduced mortality in humans and promote metabolic health and extended lifespan in rodents. Many of the benefits of protein restriction on metabolism and aging are the result of decreased consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine.

Here, we discuss the emerging evidence that BCAAs are critical modulators of healthy metabolism and longevity in rodents and humans, as well as the physiological and molecular mechanisms that may drive the benefits of BCAA restriction. Our results illustrate that protein quality - the specific composition of dietary protein - may be a previously unappreciated driver of metabolic dysfunction and that reducing dietary BCAAs may be a promising new approach to delay and prevent diseases of aging.

Link: https://doi.org/10.1111/acel.13626

Researchers have for some time investigated the effects of transfusing materials from young animals to old animals, largely blood fractions such as blood plasma, but also other line items such as samples of the gut microbiome, thymic tissue, and so forth. The work on blood and plasma transfusions from young to old has proven disappointing in comparison to parabiosis, in the sense that results have been mixed, both in mice and in human trials. Transferring gut microbes to rejuvenate the aged intestinal microbiome looks much more promising.

In today's research materials, scientists report on a more challenging procedure, the transfer of cerebrospinal fluid between mice. Young cerebrospinal fluid improves brain function in old mice, leading to benefits to memory. Based on watching more than a decade of debate over the mechanisms involved in the way in which young blood may benefit old animals, a debate that is still very much ongoing, I expect that it will no doubt be some years before the scientific community comes to a good understanding of the mechanisms involved in improvements to cognitive function resulting from exposure to young cerebrospinal fluid.

Young brain fluid improves memory in old mice

Cerebrospinal fluid (CSF) from young mice can improve memory function in older mice. A direct brain infusion of young CSF probably improves the conductivity of the neurons in ageing mice, which improves the process of making and recalling memories. The researchers also isolated a protein from the CSF cocktail that another analysis had suggested was a compelling candidate for improving memory: fibroblast growth factor 17 (Fgf17). Infusion of Fgf17 had a similar memory-restoring effect to infusing CSF. Furthermore, giving the mice an antibody that blocked Fgf17's function impaired the rodents' memory ability.

It took more than a year to perfect the process of collecting CSF and infusing it into another brain. Collection is extremely challenging, and has to be done with precision. Any blood contamination will ruin the fluid. Pressure in the brain is a delicate balance, so infusion must be slow and in a specific location within the brain: the cerebral ventricle. The delicate procedure might pose challenges for use in people.

Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17

Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures.

We identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.

Nerve tissue is not capable of significant regeneration in mammals, but the existing limited capacity for regrowth is further diminished with age. Researchers here show that one of the major classes of T cell of the adaptive immune system causes a meaningful fraction of this diminished regenerative capacity. Prevent these T cells from engaging with injured tissue and nerve regeneration is improved as a result, at least in mice. The approach used here may form the basis for an approach to greater recovery following injury in older people, and possibly even improved maintenance of nervous system tissue in later life.

Axonal regeneration and neurological functional recovery are extremely limited in the elderly. Consequently, injuries to the nervous system are typically followed by severe and long-term disability. We hypothesized that injuries to the aged nervous system would be followed by unique molecular and cellular modifications that would contribute to aging-dependent regenerative decline. To this end, molecular and cellular signatures associated with aging and injury to the nervous system were systematically investigated by performing RNA sequencing from dorsal root ganglia (DRG) in a well-established model of sciatic nerve injury in young versus aged mice.

Initial analysis of RNA sequencing data identified that aging was mainly associated with a marked increase in T cell activation and signaling in DRG after injury. Subsequent experiments demonstrated that aging was associated with increased inflammatory cytokines in DRG both preceding and following sciatic nerve injury. Specifically, we found that lymphotoxin β was required for the phosphorylation of NF-κB that drives the expression of the chemokine CXCL13 in DRG sensory neurons. CXCL13 attracted CD8+ T cells that expressed the CXCL13 receptor CXCR5 in proximity to neurons that act as antigen-presenting cells by overexpressing major histocompatibility complex class I (MHC I) after injury. The engagement of CXCR5+CD8+ T cells with MHC I-expressing sensory neurons activated caspase 3, which leads to regenerative failure.

Neutralization of CXCL13 with monoclonal antibodies reduced the recruitment of CXCR5+CD8+ T cells to the DRG and restored the regenerative ability of sciatic sensory axons in aged mice to levels comparable to those found in young animals. CXCL13 antagonism also significantly promoted skin reinnervation and neurological recovery of sensory function.

Link: https://doi.org/10.1126/science.abd5926

Here find an interview with researcher João Pedro de Magalhães, nowadays involved with a new cellular reprogramming company as well as ongoing research programs in the UK. One of the more interesting parts is the commentary on rejuvenation versus slowing aging, noted below. I agree that terminology, definition, and measurement are challenges at the moment. But I would say that he is overly conservative on the point of whether or not rejuvenation can be produced in mammals, given the extensive evidence for senolytic therapies to reverse aspects of aging and the progression of specific age-related diseases.

You could argue that there are some really simple model systems where we can reverse aging. You could also argue that we can reverse aging in human cells with telomerase and cellular reprogramming with Yamanaka factors, but whether that applies to whole organs is a completely different question. The jury is still out on whether we can actually reverse aging in mammals.

I think this might be a terminology issue. If you take an obese individual, and this individual goes on a diet, they will be healthier. Their risks from various age-related diseases are going to decrease because of the diet, but that doesn't mean that this person has been rejuvenated, it just means that a lifestyle intervention improved their health.

A lot of times, you can have interventions that improve health and maybe ameliorate elements of epigenetic clocks without necessarily doing anything about the process of aging. I think we've had this problem in the field for quite a long time - that you can have interventions that increase longevity without necessarily retarding aging, just because they're healthy. Do obese individuals age faster? I wouldn't readily assume so, although some of my colleagues may disagree with me.

You can have interventions, pharmacological interventions, for instance, that extend lifespan, but don't slow down aging in humans and even in model systems. Mice mostly die of cancer, and if you have a drug that prevents cancer, the mice are going to live longer. It doesn't mean aging has been retarded, even though longevity has increased. The problem we have in the field is what do those various interventions mean? Do they really slow aging, do they reverse aging, or are they just healthy? That's why we sometimes need to be more careful about what we are claiming to have achieved.

How would you show something like aging reversal? To me, there's still a question mark on it. I think you must have some pretty strong evidence for it - functional evidence, molecular evidence. It has to be something quite substantial to prove that you've reversed aging in a mammalian organism, that you've rejuvenated a tissue. I think that would require some pretty substantial evidence which I haven't seen yet. Going back to the question, in complex models, such as mammals - no, I don't think we have really reversed aging.

Link: https://www.lifespan.io/news/joao-pedro-de-magalhaes-on-reprogramming-and-aging-theories/

Naked mole-rats exhibit a maximum life span that is many times longer than is the case for similarly sized mammals. Further, they are negligibly senescent, showing few age-related declines in function across much of that lengthy life span. That includes maintenance of stem cell populations and regenerative capacity, as well as a near immunity to cancer. Accordingly, the research community is very interested in uncovering the genetic and biochemical differences that allow naked mole-rats to achieve these desirable outcomes.

In today's open access paper, the authors report on their investigation of the biochemistry and aging of naked mole-rat skin. The skin in this species, like other organs, shows few signs of degenerative aging in comparison to other mammals. The maintenance of stem cell populations may be one of the more important aspects of this resilience to aging, but there are a few other surprises. Clearly some gene expression in the skin is changing in the latter half of life, but that does not appear to greatly impact the more important functions.

It is interesting to speculate as to how it is that gene expression can change while function remains youthful. What is actually changing under the hood? For example, it is known that naked mole-rats do accumulate senescent cells with age, but those senescent cells do not exhibit the harmful behavior found in other mammals. Further, naked mole-rats show signs of oxidative damage to cells with age, but that damage doesn't appear to produce the consequences observed in other mammals.

Single-cell transcriptomics reveals age-resistant maintenance of cell identities, stem cell compartments and differentiation trajectories in long-lived naked mole-rats skin

Constantly exposed to both internal and environmental stresses such as UV radiation or air pollutants, the skin ages and undergo profound changes in its appearance and functions. Indeed, aged skin undergoes gradual structural and functional degeneration, leading to thinning of epidermal and dermal layers, loss of elasticity, wrinkling, and dryness. These changes are responsible for delayed wounding, more frequent infections, pruritus, enhanced allergen/irritant penetrations with variable degree of dermatitis and eventually carcinogenesis. In rodents and humans, these phenomena have been partially attributed to loss or lineage skewing of keratinocytes stem cells and immune cells, and/or the regulation of their niches, altering normal homeostasis and tissue repair.

Naked mole-rats (NMRs) are small poikilothermic and hairless rodents native to East Africa, where they live underground in eusocial colonies. These mouse-sized rodents live almost five times longer than expected on the basis of body size, with a maximum lifespan exceeding 37 years in captivity and up to 17 years in their natural habitat. Despite being the longest-lived rodent, NMR do not show any increase in age-specific hazard of mortality in defiance of Gompertz's law and all of the classical signs of aging such as decreased fertility, muscle atrophy, bone loss, changes in body composition or metabolism seem to be mostly absent in these animals.

We used single-cell RNA-sequencing (scRNA-seq), to obtain the unbiased molecular RNA profile of the NMR epidermal cell populations. By profiling 10,000+ cells from skin epidermis in young and older NMR, we found that epidermal compartments and cell populations, especially the stem cells pool, remained unaffected despite aging. Igfbp3, expressed by keratinocyte stem cells and known to play a major role during epidermal homeostasis, was found upregulated in older animals, contrary to what is observed in other species. In addition, functional skin healing experiments revealed that NMR skin healing closure was similar in young and older animals.

In recent years, researchers have noted that YAP upregulation suppresses cellular senescence in a number of different cell populations. While YAP upregulation appears to have other effects, for example on cell adhesion, relevant to cancer development, the fact that it suppresses cellular senescence means that it will likely show benefits in many different age-related conditions. That doesn't mean it is any better a choice than established senolytics that clear senescent cells, of course.

Emerging evidence has shown that senescent astrocytes are involved in initiating and promoting the progression of Alzheimer's disease (AD). Senescent astrocytes exhibit expression of senescence-associated secretory phenotype (SASP). It has been reported that the number of senescent astrocytes in the frontal cortex of AD patients is significantly higher than that of non-AD adults with similar ages. Accumulation of senescent astrocytes leads to massive secretion of SASP factors, reduces amyloid-β clearance, promotes aggregation of insoluble tau. Elimination of these senescent glial cells, including astrocytes, prevents the hyperphosphorylation of tau protein, neurofibrillary tangles, and cognitive hypofunction.

Yes-associated protein (YAP), as a co-activator and multi-functional protein, is a critical effector of the Hippo pathway, and has been shown to inhibit the senescence of various types of cells. Recently, we have found that YAP is down-regulated and inactivated in senescent astrocytes, not only in cultured senescent astrocytes, but also in hippocampal astrocytes of the aging mice and AD model mice, in a Hippo pathway-dependent manner, indicating a role of YAP in astrocytic senescence.

Cyclin-dependent kinase 6 (CDK6), as a downstream molecule of YAP, is decreased in YAP knockout astrocytes in vivo and in vitro, and over-expression of CDK6 partially rejuvenates YAP knockout astrocytes, indicating that YAP inhibits astrocytic senescence through the CDK6 signaling. Moreover, activation of YAP improves the cognitive decline of AD model mice. This evidence exhibits the positive potential of the YAP-CDK6 pathway in restraining astrocytic senescence in AD.

Link: https://doi.org/10.18632/aging.204045

Cardiovascular disease is responsible for a sizable fraction of human mortality, with atherosclerosis as the most important single cause of death in our species. Given this, it is perhaps not surprising to find genetic variants thought to contribute to differences in life expectancy between individuals also involved in the mechanisms of cardiovascular aging, dysfunction, and disease.

Aging is an archetypical complex process influenced by genetic and environmental factors. Genetic variants impart a gradient of effect sizes, albeit skewed toward those with small effect sizes. On one end of the spectrum are the rare monogenic premature aging syndromes, such as Hutchinson Gilford Progeria Syndrome, whereby single nucleotide changes lead to rapidly progressive premature aging. On the end of the spectrum is the complex, slowly progressive process of living to an arbitrary-defined old age, i.e., longevity.

Whereas the genetic basis of rare premature aging syndromes has been elucidated, only a small fraction of the genetic determinants of longevity and life span, time from birth to death, have been identified. The latter point to the complexity of the process and involvement of myriad of genetic and non-genetic factors and hence, the diluted effect of each determinant on longevity. The genetic discoveries point to the involvement of DNA damage and activation of the DNA damage response pathway, particularly in the premature aging syndromes. Likewise, the insulin/insulin-like growth factor 1/mTOR/FOXO pathways have emerged as major regulators of life span.

A notable fraction of the genetic variants that are associated with life span is also associated with age-related cardiovascular diseases, such as coronary artery disease and dyslipidemia, which places cardiovascular aging at the core of human life span. The clinical impact of the discoveries pertains to the identification of the pathways that are involved in life span, which might serve as targets of interventions to prevent, slow, and even possibly reverse aging.

Link: https://doi.org/10.20517/jca.2022.06

Lipofuscin is a mix of many forms of persistent metabolic waste that accumulates with age in the lysosomes of long-lived cells, such as those of the central nervous system. This degrades the effectiveness of cellular recycling mechanisms, as they depend upon the delivery of materials to lysosomes, where they are broken down. A lysosome is a membrane packed with molecular tools to break down near everything a cell will encounter, but (a) it struggles with some compounds, and (b) becomes impaired in old tissues, and hence the existence of lipofuscin.

Targeted removal of lipofuscin is an important strategy in the rejuvenation toolkit. As of yet only partially effective approaches are available, unfortunately. Like the example here, these depend on adjusting metabolism in ways that provoke greater cellular housekeeping efforts, more efficient lysosomal function.

Plausibly, this will only work for some of the many different problem molecules that make up lipofuscin, those are are less resilient to being broken down, that only accumulate to cause pathology as a result of age-related declines in cellular maintenance. While we have the one impressive example of liver function rejuvenation as a result of improving lyosomal function with LAMP2A upregulation, in general the strategy of upregulating cellular maintenance doesn't work as well to extend life in long-lived species as it does in short-lived species. This is well demonstrated in the few examples we can compare directly, such as the practice of calorie restriction.

Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan

Lipofuscin is a representative biomarker of aging that is generated naturally over time. Remofuscin (soraprazan) improves age-related eye diseases by removing lipofuscin from retinal pigment epithelium (RPE) cells. In this study, the effect of remofuscin on longevity in Caenorhabditis elegans and the underlying mechanism were investigated. The results showed that remofuscin significantly extended the lifespan of C. elegans compared with the negative control. Aging biomarkers were improved in remofuscin-treated worms.

The expression levels of genes related to lysosomes (lipl-1 and lbp-8), a nuclear hormone receptor (nhr-234), fatty acid beta-oxidation (ech-9), and xenobiotic detoxification (cyp-34A1, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35C1, gst-28, and gst-5) were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. elegans with loss-of-function mutations (lipl-1, lbp-8, nhr-234, nhr-49, nhr-8, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A5, and gst-5), suggesting that these genes are associated with lifespan extension in remofuscin-treated C. elegans.

In conclusion, remofuscin activates the lysosome-to-nucleus pathway in C. elegans, thereby increasing the expression levels of xenobiotic detoxification genes resulted in extending their lifespan.

This open access paper presents an interesting view on the interaction between infectious viruses and cellular senescence, with a focus on neurodegenerative disease. Senescent cells are better hosts for viral replication than other cells, and thus viruses have evolved to provoke cells into becoming senescent. That in turn has the potential to produce lasting harm in an infected individual by increasing the burden of senescent cells. Chronic inflammation is an important factor in the progression of neurodegeneration, and senescent cells secrete pro-inflammatory signals. Indeed, some view tauopathies such as Alzheimer's disease as the consequence of a feedback loop between cellular senescence, inflammation, and tau aggregation: once established in some way, it will keep running independently of its origin.

A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia, multi-nucleate cells resulting from fusion.

Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau, and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia.

In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a "decentralized" information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

Link: https://doi.org/10.3389/fcimb.2022.845580

Researchers here report on a study showing that lower physical performance in old age correlates with only one of a small panel of selected blood markers of inflammation. It is expected that a greater burden of chronic inflammation will cause a more rapid decline in later life, including the loss of strength and resilience leading into frailty. Inflammation and its interaction with tissue function is sufficiently complex a topic, and sufficiently varied from individual to individual, that we might expect to see mixed results like these, however.

Maintenance of physical performance is essential for achievement of healthy aging. A few studies have explored the association between inflammatory markers and physical performance in older adults with inconclusive results. Our aim was to analyze the association of tumor necrosis factor-alpha (TNF-α), Interleukin-10 (IL-10), and C-reactive protein (CRP) with physical performance in a sample of older adults in rural settings of Mexico. Our study comprised 307 community-dwelling older men and women who participated in the third wave of the Rural Frailty Study.

In comparison with the normal physical performance group, low physical performance individuals mainly were female, older, more illiterate, more hypertensive, fewer smokers, and had higher CRP levels. The logistic model results showed a significant association between the 3rd tertile of CRP and low physical performance (odds ratio = 2.23). IL-10 and TNF-α levels did not show a significant association. The results of this study were thus mixed, with a significant association of physical performance with higher CRP levels but nonsignificant with IL-10 and TNF-α. Further studies with improved designs are needed by incorporating a broader set of inflammatory markers.

Link: https://doi.org/10.1186/s12877-022-03091-7

The prevailing view of Alzheimer's disease continues to be the amyloid cascade hypothesis, that a slow age-related accumulation of misfolded amyloid-β causes sufficient dysfunction to set the stage for later pathology involving senescent cells, chronic inflammation, and aggregation of altered tau protein. That later pathology is much more destructive, self-sustaining enough for removal of amyloid-β, now successfully achieved in a number of immunotherapy clinical trials, to be of little use to patients.

It remains that case that the research community sees removal of amyloid-β as a potential way to prevent the development of Alzheimer's disease, assuming sufficiently early and sustained intervention to maintain low levels of amyloid-β aggregation throughout life. Today's open access paper discusses an immunization approach: direct the immune system to destroy excess amyloid-β by provoking it into recognizing a part of the amyloid-β protein as foreign.

The interesting unresolved question continues to be why amyloid-β aggregation is an age-related process. A growing faction within the research community question whether amyloid-β accumulation is actually an important contributing cause of Alzheimer's disease, versus being a side-effect of other, more relevant processes. For example, amyloid-β is an anti-microbial peptide, a component of the innate immune system, and it may be that increased levels of amyloid-β are a feature of persistent vital infection that drives chronic inflammation, where that inflammation is the true driving pathology.

Study preserves memory in mice, offering promising new basis for active immunization against Alzheimer's disease

Researchers have discovered a possible new approach to immunization against Alzheimer's disease (AD). Their method uses a recombinant methionine (Met)-rich protein derived from corn that was then oxidized in vitro to produce the antigen: methionine sulfoxide (MetO)-rich protein. This antigen, when injected to the body, goads the immune system into producing antibodies against the MetO component of beta-amyloid, a protein that is toxic to brain cells and seen as a hallmark of Alzheimer's disease.

"As we age, we have more oxidative stress, and then beta-amyloid and other proteins accumulate and become oxidized and aggregated - these proteins are resistant to degradation or removal. In a previous 2011 published study, I injected mouse models of Alzheimer's disease with a similar methionine sulfoxide-rich protein and showed about 30% reduction of amyloid plaque burden in the hippocampus, the main region where damage from Alzheimer's disease occurs."

The MetO-rich protein used for the vaccination of AD-model mice is able to prompt the immune system to produce antibodies against MetO-containing proteins, including MetO-harboring beta-amyloid. The introduction of the corn-based MetO-rich protein (antigen) fosters the body's immune system to produce and deploy the antibodies against MetO to previously tolerated MetO-containing proteins (including MetO-beta-amyloid), and ultimately reduce the levels of toxic forms of beta-amyloid and other possible proteins in brain.

Protective Effects against the Development of Alzheimer's Disease in an Animal Model through Active Immunization with Methionine-Sulfoxide Rich Protein Antigen

The brain during Alzheimer's disease (AD) is under severe oxidative attack by reactive oxygen species that may lead to methionine oxidation. Oxidation of the sole methionine of beta-amyloid (Aβ), and possibly methionine residues of other extracellular proteins, may be one of the earliest events contributing to the toxicity of Aβ and other proteins in vivo. In the current study, we immunized transgenic AD (APP/PS1) mice at 4 months of age with a recombinant methionine sulfoxide (MetO)-rich protein from Zea mays (antigen). This treatment induced the production of anti-MetO antibody in blood-plasma that exhibits a significant titer up to at least 10 months of age.

Compared to the control mice, the antigen-injected mice exhibited the following significant phenotypes at 10 months of age: better short and long memory capabilities; reduced Aβ levels in both blood-plasma and brain; reduced Aβ burden and MetO accumulations in astrocytes in hippocampal and cortical regions; reduced levels of activated microglia; and elevated antioxidant capabilities (through enhanced nuclear localization of the transcription factor Nrf2) in the same brain regions.

A growing body of evidence implicates the presence of senescent cells in the development of vascular calcification. Calcification arises as cells in blood vessel walls inappropriately take on the characteristics of bone cells. Senescent cells produce inflammatory signaling that contributes to these and other detrimental changes, and much of that signaling is carried in extracellular vesicles, membrane-wrapped packages of molecules that pass between cells in tissue. The direct solution to this problem is targeted removal of senescent cells, via senolytic therapies, but that isn't stopping researchers from mapping the way in which senescent cell signaling causes dysfunction.

Vascular calcification is an irreversible pathological process associated with a loss of vascular wall function. This process occurs as a result of aging and age-related diseases, such as cardiovascular and chronic kidney diseases, and leads to comorbidities. During these age-related diseases, the endothelium accumulates senescent cells, which stimulate calcification in vascular smooth muscle cells. Currently, vascular calcification is a silent pathology, and there are no early diagnostic tools. Therefore, by the time vascular calcification is diagnosed, it is usually untreatable.

Some mediators, such as oxidative stress, inflammation, and extracellular vesicles, are inducers and promoters of vascular calcification. They play a crucial role during vascular generation and the progression of vascular calcification. Extracellular vesicles, mainly derived from injured endothelial cells that have acquired a senescent phenotype, contribute to calcification in a manner mostly dependent on two factors: (1) the number of extracellular vesicles released, and (2) their cargo. In this review, we present state-of-the-art knowledge on the composition and functions of extracellular vesicles involved in the generation and progression of vascular calcification.

Link: https://doi.org/10.3389/fcvm.2022.854726

Researchers here suggest that lifestyle choices mediate an observed association between desired length of life, as assessed in middle-age, and actual length of life. Those people who want to live longer will do at least something to help achieve that goal, such as avoiding obesity and lack of exercise. Or perhaps those people already suffering from a more rapid pace of aging are, on balance, disenchanted at the thought of a future decline that seems more profound - though the researchers here claim to have controlled for that contribution, given the existence of health data at the time of survey.

Desired longevity represents how strongly people esteem possible extensions of their own lifetime. The association between desired longevity and mortality risk has been reported in only one prospective study, which examined a small sample of older participants. We aimed to examine the hypothesis that desired longevity at middle-age predicted long-term survival.

In the prospective cohort study, residents aged 40-64 years were asked how long they would like to live and asked to choose one from three options: longer than, as long as, or shorter than the life expectancy. 39,902 residents were recruited to the study. Risk of all-cause mortality was significantly higher in the "shorter than" group (hazard ratio 1.12). The association was independent of sex, age, marital status, education, medical history, and health status. Regarding cause of death, mortality risk of cancer (hazard ratio 1.14) and suicide (hazard ratio 2.15) were also higher in the "shorter than" group. The unhealthy lifestyle mediated this association with all-cause mortality by 30.4%.

In conclusion, shorter desired longevity was significantly associated with an increased risk of all-cause mortality, and mortality from cancer and suicide. Lifestyle behaviors particularly mediated this association.

Link: https://doi.org/10.2188/jea.JE20210493

How much of the improvement in health and extension of life span produced by calorie restriction in mouse studies is due to lowered calorie intake versus length of time spent fasting between meals? In most past studies, calorie restricted mice were fed once a day, resulting in long periods of fasting and hunger-induced metabolic changes between meals. It may be that this timing is important, and of late researchers have started to run studies intended to assess this question.

Data obtained to date strongly suggests that, yes, time of fasting does matter and does contribute to health and longevity benefits in mice independently of reduced calorie intake. Today's research materials further support that conclusion. The authors report on a study in which calorie restricted mice are fed at different intervals. Allowing these mice to eat throughout the day reduces the gain in life span usually observed in calorie restriction studies.

Active phase calorie restriction enhances longevity

Timing feedings to match the active period of the circadian cycle extended the life span of lab mice more than three times as much as caloric restriction alone. Mice that ate as much and whenever they wanted lived nearly 800 days median life span - an average period for their species. Restricting calories but making food available around the clock extended their lives only 10% to 875 days despite restricting calories by 30-40%. Restricting this reduced-calorie diet to the inactive period of the circadian cycle boosted lifespan by nearly 20% to an average of 959 days. Offering the low-calorie diet only during the active period of the cycle extended their median life span to about 1,068 days, an increase of almost 35% over the unrestricted eaters.

Further investigation showed that the mice that lived the longest had significantly better metabolic health, with higher insulin sensitivity and blood sugar stability. They tended to get diseases that killed the younger mice, such as various forms of cancer, at far more advanced ages. Gene expression experiments showed fewer changes in the activity of genes associated with inflammation, metabolism and aging in the long-lived animals compared to the shorter-lived ones.

Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice

Caloric restriction (CR) prolongs lifespan, yet the mechanisms by which it does so remain poorly understood. Under CR, mice self-impose chronic cycles of 2-hour-feeding and 22-hour-fasting, raising the question whether calories, fasting, or time of day are causal. We show that 30%-CR is sufficient to extend lifespan 10%; however, a daily fasting interval and circadian-alignment of feeding act together to extend lifespan 35% in male C57BL/6J mice. These effects are independent of body weight. Aging induces widespread increases in gene expression associated with inflammation and decreases in expression of genes encoding components of metabolic pathways in liver from ad lib fed mice. CR at night ameliorates these aging-related changes. Thus, circadian interventions promote longevity and provide a perspective to further explore mechanisms of aging.

Researchers here coin a term, cellular exercise, to describe the benefits resulting from mild cellular stress and the consequent housekeeping responses. Increased cellular maintenance activities in response to mild stress lead to a net improvement in cell and tissue function. In short-lived laboratory species, interventions that provide chronic mild stress, such as calorie restriction, improve long term health and increase life span. Interventions based on this approach may be less interesting in long-lived species such as our own, however, given that, for example, calorie restriction provides up to 40% extension of life in mice, but at most a few years in humans.

"Cellular exercise" is a concept where low levels of cellular stress, induced by chronic calorie restriction or physical exercise, can lead to molecular adaptations on the cellular level that can protect the body from cancer and cardiovascular disease. An increase in reactive oxygen species induced by caloric restriction and physical exercise can produce improvements in redox equilibrium that can result in a more adaptive capable cell.

Insulin-like growth factor-1 has a dual effect wherein calorie restriction downregulates insulin-like growth factor-1 inhibiting pathways of carcinogenic proliferation and metastasis and physical exercise can upregulate insulin-like growth factor-1 to promote mitochondrial biogenesis and protein synthesis thereby strengthening healthy muscle against hypoxic ischemic damage and muscular regenerative properties. Transcription of Nrf2 is also upregulated to attenuate inflammation induced by nuclear factor-κB, AMPK upregulates genes through PGC-1α to prevent sarcopenia and induce lipolysis.

This molecular melody is the complex composition that explains the cellular adaption that occurs to strengthen the body from cognitive dysfunction, cardiometabolic failure and carcinogenic implantation and metastasis via mechanisms of redox equilibrium, oxidative protection, attenuation of inflammation, and attenuation of carcinogenic proliferation and growth.

Link: https://doi.org/10.1016/j.nut.2022.111629

Researchers have explored a number of mitochondria-derived peptides as a basis for treatments in the context of aging. These peptides are created from fragments of genes in the mitochondrial DNA, released from the cell, and appear to be involved in a range of mechanisms relevant to declining function in aging. Is it possible to supply such peptides as a therapy in order to produce benefits in an aged metabolism? A number of groups working towards that goal, on the basis of data in animal studies and humans patients.

The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1-6.

MDPs have been extensively studied in the context of aging. Three MDPs have been studied in the context of age-related diseases: humanin, MOTS-c, and SHLP2. Humanin has been shown to mitigate Alzheimer's disease pathology in rodents, and its levels and genetic variation associate with age and cognition. MOTS-c has been described as an exercise mimetic and prevents muscle atrophy in mice, and its levels and genetic variation associate with age and type 2 diabetes (T2D). SHLP2 functions as a mitochondrial modulator and protein chaperone, and its levels associate with age and prostate cancer.

In addition to their ability to attenuate age-related diseases, MDPs have promoted lifespan and healthspan. Humanin is the best-conserved MDP and is found in as diverse species as humans, naked mole rats, and nematodes. Overexpression of humanin increased lifespan in nematodes, and this was dependent on FOXO. Additionally, humanin has increased autophagy in cells, and this increase in autophagy was also required for the lifespan extension in the transgenic worms. The second approach was to initiate a longevity experiment in mice in which we injected middle-aged (18-month-old) female mice with humanin twice a week. Although lifespan was not increased - likely because of humanin's short half-life of approximately 20 minutes - healthspan measures such as memory and metabolic parameters improved. Thus, humanin is sufficient to increase lifespan and healthspan in model organisms, and an optimized dosing of humanin may lead to increases in lifespan in more complex organisms.

Link: https://doi.org/10.1172/JCI158449

Today's open access paper reports on an effort to measure the effects of microbial rejuvenation on tissue function in mice. Fecal microbiota transplantation can reverse the aging of the gut microbiome, at least when carried out in animal studies, and as measured by the detrimental shift in microbial populations that takes place with age. Transplanting microbes from a young gut into an old gut reverses many of the alterations in relative abundance of specific microbial species, and has been shown to improve health and extend life span in some species.

In an old mouse, or human, there are fewer microbes producing beneficial metabolites, and more inflammatory microbes that provoke the immune system. This contributes to declining tissue function and increased chronic inflammation. Interestingly, this shift may be largely due to the aging of the immune system, and a progressive failure to sufficiently garden the gut microbiome, but there may be other contributing causes as well. How large an effect on function is produced by the aging of the gut microbiome versus other issues in aging? The fastest way to answer that question is to restore a youthful gut microbiome and assess the results.

Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain

Altered intestinal microbiota composition in later life is associated with inflammaging, declining tissue function, and increased susceptibility to age-associated chronic diseases, including neurodegenerative dementias. Here, we tested the hypothesis that manipulating the intestinal microbiota influences the development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina.

Using fecal microbiota transplantation (FMT), we exchanged the intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice. Whole metagenomic shotgun sequencing and metabolomics were used to develop a custom analysis workflow, to analyze the changes in gut microbiota composition and metabolic potential. Effects of age and microbiota transfer on the gut barrier, retina, and brain were assessed using protein assays, immunohistology, and behavioral testing.

We show that microbiota composition profiles and key species enriched in young or aged mice are successfully transferred by FMT between young and aged mice and that FMT modulates resulting metabolic pathway profiles. The transfer of aged donor microbiota into young mice accelerates age-associated central nervous system (CNS) inflammation, retinal inflammation, and cytokine signaling and promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability. Conversely, these detrimental effects can be reversed by the transfer of young donor microbiota.

These findings demonstrate that the aging gut microbiota drives detrimental changes in the gut-brain and gut-retina axes suggesting that microbial modulation may be of therapeutic benefit in preventing inflammation-related tissue decline in later life.

The chronic raised blood pressure of hypertension is both (a) driven by the stiffening of blood vessel walls and (b) causes further detrimental restructuring of blood vessel walls, such as thickening of the intimal and medial layers. Researchers here explore the chains of cause and effect that lead to this outcome, mediated by increased inflammatory signaling and the presence of macrophages drawn into the blood vessel walls.

Persistent hypertension can cause long-lasting changes in the structure of vascular smooth muscle cells (the cells making up the walls of blood vessels) through a process called "vascular remodeling." If left unchecked, this restructuring can stiffen arterials walls, which lose their ability to adjust their size appropriately. This, in turn, leads to arteriosclerosis and increases the risk of cerebrovascular disease.

Why and how hypertension triggers vascular remodeling is not entirely clear. Scientists have shown that macrophages, a type of white blood cells that kill foreign bodies, are involved in the transformation. Specifically, the macrophages accumulate within blood vessel walls from outside the vessels and cause chronic inflammation. However, the underlying mechanism that orchestrates this process remains unknown.

A new study recently investigated a mechanism known as "excitation-transcription (E-T) coupling" in vascular smooth muscle cells. Although E-T coupling occurs in vascular smooth muscle cells after an influx of Ca2+ under high pressure, not much was known about how it happens, what genes are triggered, and the role it plays in our bodies.

By taking a detailed look at the genes promoted by E-T coupling and observing their effects when blocked or amplified, the researchers made some important discoveries. Firstly, some of these genes were related to chemotaxis, the phenomenon by which cells movement is triggered and directed by chemical stimuli. This helped explain the accumulation of macrophages in blood vessel walls from outside the vessels. Additionally, these genes promoted the remodeling of the medial layer of arteries, where vascular smooth muscle cells reside and control blood flow through contraction and expansion. "Taken together, our results explain how E-T coupling caused by high pressure in vascular smooth muscle cells can modulate macrophage migration and subsequent inflammation, altering the vascular structure,"

Link: https://www.eurekalert.org/news-releases/950487

Here find a popular science interview with Thomas Kirkwood on his contributions to present thought on how and why degenerative aging evolved to be near universal in living organisms. At the high level, what we think that we know about the evolution of aging does to some degree inform the approaches taken to treat aging: in advance of firm data, should we expect one strategy to be better than another, and thus prioritize it?

"I wondered why cells allow damage to build up in the first place. And the idea came to me then, which was the realisation that it takes energy to combat the build-up of damage. There are maintenance and repair processes, proofreading mechanisms to make sure you don't do things wrong in the first place, and then clearance mechanisms to make sure you clean up your mistakes and get rid of them. And all of that costs energy."

"I started thinking that maybe this was the answer to question of why we age and die - because it was never evolutionarily worthwhile to invest enough in the maintenance and repair processes of the body to keep our cells from going on indefinitely. The essence of the theory is simply that, under the pressure of natural selection, organisms invest enough in the maintenance of somatic cells to keep them going for long enough to allow us to grow and reproduce and make the next generation, but it was never worthwhile for them to invest enough for those cells to last indefinitely."

"The theory says that aging will occur, because the whole repertoire of maintenance and repair systems will be tuned to a level that allows damage to build up. That has interesting implications in that it tells us that, from an evolutionary perspective, we should not expect there to be a single mechanism of aging. Very often you'll find groups of scientists that are championing one or other mechanism - so it's all telomeres, or it's all DNA mutations, or proteostasis collapse, or mitochondria, or cellular senescence. But the theory tells us is that it is not one mechanism versus another mechanism but that they work simultaneously, and they work in synergistic ways."

Link: https://longevity.technology/tom-kirkwood-aging-is-neither-inevitable-nor-necessary/

Epigenetic clocks are produced by identifying characteristic shifts in epigenetic marks with age, the decorations on the genome that control gene expression. It remains unclear as to the exact relationship between specific epigenetic marks and the underlying damage and dysfunction of aging, and so it remains unknown as to how comprehensively epigenetic clocks reflect the processes of aging: do all of the processes of aging contribute, or only some of them? If the latter, it will be hard to use epigenetic clocks to assess the quality of potential rejuvenation therapies. Removing that uncertainty will require a great deal of further work.

When epigenetic age is higher than chronological age, this is referred to as accelerated epigenetic age. It is thought to reflect a greater burden of the underlying cell and tissue damage that causes aging, but of course the uncertainty remains as to whether this is a full versus selective representation of the state of health for any given epigenetic clock - any given combination of epigenetic marks, in other words. Are there aspects of aging that contribute little to epigenetic age?

With that in mind, researchers here note that a first pass at analysis of cancer incidence and accelerated epigenetic age found little in the way of firm correlations. This is interesting, as (a) cancer risk is very robustly age-associated, (b) the risk of a number of other age-related conditions does correlate to accelerated epigenetic age, and (c) recent work suggests that incidence of serious mutational damage causes epigenetic change, so one might expect a greater pace of mutational damage to lead to both more cancer and more epigenetic aging.

Cancer: The aging epigenome

Age is a prominent risk factor for most types of cancer. Cancer risk increases with age, in part, because genetic mutations that arise from DNA replication errors and exposure to environmental carcinogens accumulate as we get older. Aging also alters the epigenome, the chemical marks spread across DNA that help switch genes on or off by altering how the genome is packaged. For instance, the addition of a methyl group to DNA can play a role in compressing the nearby DNA sequence so it can no longer be accessed by the cell's machinery. Epigenetic modifications, including DNA methylation, have also been shown to contribute to the development of cancer. However, the potential impact of age-related epigenetic changes on cancer development has not been fully characterized.

It has been hypothesized that people whose epigenetic age is greater than their age in years - a phenomenon known as accelerated aging - may be at higher risk of age-related diseases, including cancer. However, previous studies linking accelerated epigenetic aging and cancer have produced mixed results. Now a team has taken a different approach. Instead of associating a person's risk of cancer with epigenetic clock estimates, they correlated it against genetic variations that are known to influence these algorithms.

The results did not show many clear relationships between the epigenetic aging clocks and risk for the various types of cancer studied. The most promising finding was an association between the GrimAge clock and colorectal cancer. The GrimAge clock was not designed to predict age alone, but also reflects the effects of smoking and other mortality-related epigenetic features. Thus, the interpretation of this association is not straightforward, as this clock may capture the effects of environmental or lifestyle factors on the epigenome. One caution is that epigenetic clocks have largely been developed based on how aging affects DNA methylation in blood cells. Much less is known regarding aging and epigenetics in other tissue types, including those prone to cancer.

Ribosomes in a cell are where proteins are assembled according to a messenger RNA blueprint. Like all cellular components, ribosomes are regularly created and recycled. Reduced production of new ribosomes is a feature of calorie restriction, slowed aging accompanied by a lower output of new proteins. Further, genetic alterations that force a reduction in ribosomal biogenesis also modestly slow aging in animal studies, so it is thought that the pace of protein production is a relevant mechanism in the connection between cellular metabolism and aging. Researchers here extend this line of research into humans, looking at ribosomal function and protein production in long-lived individuals.

As a paradigm of successful human aging, long-lived individuals (LLIs) achieve extreme old age without developing serious age-related diseases (e.g., cardiovascular disease, neurodegenerative disorders, and cancer). Gene expression is thought to have a close association with the activity of processes involved in healthy aging and longevity in LLIs. Here, to find the processes displaying reduced biological activities in long-lived people, we obtained and analyzed the transcriptomes of peripheral white blood cells from 193 female LLIs and 83 gender-matched spouses of LLI children (F1SPs) from two independent Chinese longevity cohorts.

Results showed that genes related to the ribosome pathway, especially ribosomal protein genes (RPGs), were significantly down-regulated in the LLIs. We also found that most of the RPGs were positively coexpressed with the ETS1 gene, which was down-regulated in LLIs. This gene encodes a transcription factor that binds to RPG promoters, and its down-regulation leads to the reduced RPG expression. Furthermore, knockdown of ETS1 alleviated cellular senescence and suppressed RPG transcription in human dermal fibroblast (HDF) and human embryonic lung fibroblast (IMR-90) cells.

Thus, these findings reveal that decreased ribosome biogenesis caused, at least in part, by the down-regulation of ETS1 exists in certain female LLIs and may contribute to healthy aging and life span extension in long-lived people.

Link: https://doi.org/10.1126/sciadv.abf2017

Age-related decline in stem cell function is an important contributing cause of aging, and cellular senescence in stem cell populations and their supporting cells is a feature of this process. Mesenchymal stem cells are a well studied population that is not only relevant to tissue function but also widely used as a basis for stem cell treatments. These therapies also face challenges due to declining cell function and the onset of cellular senescence, occurring when stem cells are cultured and expanded for use in therapy.

Aging is a multifaceted and complicated process, manifested by a decline of normal physiological functions across tissues and organs, leading to overt frailty, mortality, and chronic diseases, such as skeletal, cardiovascular, and cognitive disorders, necessitating the development of practical therapeutic approaches.

Stem cell aging is one of the leading theories of organismal aging. For decades, mesenchymal stem/stromal cells (MSCs) have been regarded as a viable and ideal source for stem cell-based therapy in anti-aging treatment due to their outstanding clinical characteristics, including easy accessibility, simplicity of isolation, self-renewal, and proliferation ability, multilineage differentiation potentials, and immunomodulatory effects. Nonetheless, as evidenced in numerous studies, MSCs undergo functional deterioration and gradually lose stemness with systematic age in vivo or extended culture in vitro, limiting their therapeutic applications.

Even though our understanding of the processes behind MSC senescence remains unclear, significant progress has been achieved in elucidating the aspects of the age-related MSC phenotypic changes and possible mechanisms driving MSC senescence. In this review, we aim to summarize the current knowledge of the morphological, biological, and stem-cell marker alterations of aging MSCs, the cellular and molecular mechanisms that underlie MSC senescence, the recent progress made regarding the innovative techniques to rejuvenate senescent MSCs and combat aging, with a particular focus on the interplay between aging MSCs and their niche as well as clinical translational relevance. Also, we provide some promising and novel directions for future research concerning MSC senescence.

Link: https://doi.org/10.1093/stcltm/szac004

A good deal of research of late has focused on the role of the gut microbiome in aging. One portion of this part of the field covers the interactions between the gut microbiome and the brain. For example, butyrate is a metabolite generated by the gut microbiome, in declining amounts with age as the balance of microbial populations shifts. Butyrate upregulates BDNF, which in turn upregulates neurogenesis in the brain, the production of new neurons. The consensus on neurogenesis is that more of it is a good thing, and many research programs are working towards safe ways to achieve this goal.

One of the more notable age-related changes in the gut microbiome is the growth of inflammatory populations, those that provoke the immune system and cause a meaningful fraction of the chronic inflammation that is characteristic of older individuals. This inflammation contributes to the onset and progression of all of the common age-related conditions. Since the immune system is responsible for gardening the microbiome and removing these inflammatory microbes, this is a bidrectional relationship. More inflammatory microbes degrade the effectiveness of the immune system, but the dysfunctions of immune aging allow these harmful populations to run amok.

What can be done about this? In animal studies, fecal microbiota transplantation from young individuals to old individuals has been shown to reset the gut microbiome, improve health, and extend life. There are other strategies with varying degrees of evidence to support their efficacy, but this one seems the most practical, given that fecal microbiota transplantation is already used in medical practice, and thus it would be a comparatively small step to adapt it to this new use case.

Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging

It has been noticed in recent years that the unfavorable effects of the gut microbiota could exhaust host vigor and life, yet knowledge and theory are just beginning to be established. Increasing documentation suggests that the microbiota-gut-brain axis not only impacts brain cognition and psychiatric symptoms but also precipitates neurodegenerative diseases, such as Alzheimer's disease (AD).

How the blood-brain barrier (BBB), a machinery protecting the central nervous system (CNS) from the systemic circulation, allows the risky factors derived from the gut to be translocated into the brain seems paradoxical. For the unique anatomical, histological, and immunological properties underpinning its permeable dynamics, the BBB has been regarded as a biomarker associated with neural pathogenesis. The BBB permeability of mice and rats caused by GM dysbiosis raises the question of how the GM and its metabolites change BBB permeability and causes neuroinflammation and neurodegeneration (NF&ND) and brain aging, a pivotal multidisciplinary field tightly associated with immune and chronic systemic inflammation.

Gut microbiota-induced systemic chronic inflammation mainly refers to excessive gut inflammation caused by gut mucosal immunity dysregulation, which is often influenced by dietary components and age, is produced at the interface of the intestinal barrier (IB) or exacerbated after IB disruption, initiates various common chronic diseases along its dispersal routes, and eventually impairs BBB integrity to cause NF&ND and brain aging.

4-phenyl butyrate can be delivered orally, and once inside cells it mimics some of the natural chaperone molecules that aid in protein folding in the endoplasmic reticulum. Improved the quality and pace of protein folding leads to better cell function, particularly given that rising levels of endoplasmic reticulum stress and impairment in the compensatory unfolded protein response are observed in aged tissues. Addressing this issue can improve the state of tissue function in aged animals, at least to some degree, as demonstrated in the research results noted here.

As the aging population grows, the need to understand age-related changes in health is vital. Two prominent behavioral changes that occur with age are disrupted sleep and impaired cognition. Sleep disruptions lead to perturbations in proteostasis and endoplasmic reticulum (ER) stress in mice. Further, consolidated sleep and protein synthesis are necessary for memory formation. With age, the molecular mechanisms that relieve cellular stress and ensure proper protein folding become less efficient.

It is unclear if a causal relationship links proteostasis, sleep quality, and cognition in aging. Here, we used a mouse model of aging to determine if supplementing chaperone levels reduces ER stress and improves sleep quality and memory. We administered the chemical chaperone 4-phenyl butyrate (PBA) to aged and young mice, and monitored sleep and cognitive behavior. We found that chaperone treatment consolidates sleep and wake, and improves learning in aged mice. These data correlate with reduced ER stress in the cortex and hippocampus of aged mice.

Chaperone treatment increased phosphorylated CREB (p-CREB), which is involved in memory formation and synaptic plasticity, in hippocampi of chaperone-treated aged mice. Further, hippocampal overexpression of the endogenous chaperone, binding immunoglobulin protein (BiP), improved cognition, reduced ER stress, and increased p-CREB in aged mice, suggesting that supplementing BiP levels are sufficient to restore some cognitive function. Together, these results indicate that restoring proteostasis improves sleep and cognition in a wild-type mouse model of aging.

Link: https://doi.org/10.1111/acel.13598

A lot of work has gone into better understanding the roles of sirtuin 1 (SIRT1) in aging, ultimately something of a dead end, not a large enough influence on relevant areas of cellular biochemistry to produce viable treatments to slow aging. Sirtuin 6 (SIRT6), on the other hand is less well explored, but somewhat more interesting, even though it is likely still only a path towards therapies that can do not more than modestly slow aging over time. Overexpression of SIRT6 extends life in mice. One of the possible mechanisms for that extension of life is promotion of DNA repair, and a startup biotech company is working on a SIRT6 gene therapy aimed at improving DNA repair in inherited DNA repair deficiency conditions. Nonetheless, what is presently known about SIRT6 is much less than we'd like to know, as noted in this review paper.

SIRT6 has a range of post-translational modification (PTM) capabilities and is widely involved in aging, immunity, and cancer regulation. SIRT6 is a longevity protein that prevents cells, tissues, organs, and the body from aging. Although the mechanisms underlying these effects are diverse, they all involve resistance of aging by promoting of DNA damage repair, maintaining of the normal telomere structure of chromosomes, regulating of glucose and NAD+ metabolic balance, and by regulating of the senescence-associated secretory phenotype (SASP). SIRT6 can also affect the differentiation and function of immune cells by regulating PTM affecting cells or the immunometabolism. However, the role of SIRT6 in immune regulation is complex.

Although most studies have shown SIRT6 to have anti-inflammatory activity, there is no lack of evidence regarding its pro-inflammatory potential. There has been insufficient research on how SIRT6 affects inflammation by regulating immune cells; SIRT6 has rarely been studied in many immune cells including granulocytes, monocytes, B cells, natural killer (NK) cells, and NKT cells. However, according to the recent research, the SIRT6-PTM or immunometabolism axes represent new directions with research potential.

The role of SIRT6 in cancer development is complex. SIRT6 shows differential expression in cancer tissues compared with normal tissues; its expression levels may also vary among different cancers, at different stages of the same cancer, and in different cell lines of the same tumor type. It also has both positive and negative effects on the regulation of cancer. Few studies have analyzed whether SIRT6 could achieve anti-cancer effects via regulation of immune cell function. This could represent a new direction for future research. For example, it may be possible to adjust the polarization of macrophages through SIRT6 to affect tumor progression.

Taken together, these findings indicate that SIRT6 will serve as an important target candidate for regulating immunosenescence and immune cell function. Drugs designed to target SIRT6 will also make an important contribution to the fight against chronic inflammation and cancer. SIRT6, as an important regulator throughout immunosenescence, inflammaging, and cancer, is a potential target for the regulation of the immune system.

Link: https://doi.org/10.3389/fonc.2022.861334

Geroprotective therapies are those that slow aging. While true rejuvenation therapies capable of reversing aging may also fall under that broad umbrella, discussion of geroprotectors usually focuses on drugs such as mTOR inhibitors that can at least modestly slow aging in animal studies. One area of growing interest in the field is the use of epigenetic clocks to assess aging, and the degree to which the clock measurements are affected by potentially geroprotective interventions.

The challenge in epigenetic clocks - and other conceptually similar clocks - is that they are fitted to observed age-related changes in biochemical data without any understanding of what causes those changes. Perhaps characteristic epigenetic changes that take place with age reflect all of the underlying processes of aging, and perhaps they do not. Thus one cannot take any given result in the treatment of aging at face value until the specific clock has been calibrated to the specific intervention in life span studies, a lengthy prospect that entirely defeats the point of a simple measure of aging, and which has yet to be undertaken for any class of intervention.

As researchers point out here, this means that clocks, while interesting and meriting further study, must be relegated to the second tier of data for the foreseeable future. Whether or not a given intervention produces slowed aging, and is thus geroprotective, can only be assessed robustly at the present time via established measures of health and age-related disease.

Does Modulation of an Epigenetic Clock Define a Geroprotector?

The geroscience hypothesis, that the rate of aging can be changed, is indeed an exciting one, and one that will likely receive considerable attention in the future. Geroprotectors arising from studies exploring the geroscience hypothesis would undoubtedly revolutionize health care and result in dramatic societal changes, and for these reasons should be taken extremely seriously. However, the biomedical science community should be very sensitive to overenthusiasm concerning ways in which geroprotectors are vetted, since reliance on a solitary measure of aging, for example an epigenetic clock, to vet candidate geroprotectors might not be necessary. If geroprotectors, by definition, should improve health during the aging process, and health can be measured in myriad ways, then relevant trials should focus on these health measures directly.

In fact, as we have argued, it would be hard to make the case that a geroprotector that is only known or shown to modulate an epigenetic clock will extend health span or lifespan without impacting anything associated with health from traditional clinical perspectives. In addition, if one could show that a geroprotector actually does modulate age-related disease processes using routine and accepted clinical measures then the mechanism of action of that geroprotector is likely to be a key to an underlying universal aging clock. Ultimately, a purported geroprotector that has either no observable effect on many available common sense, well-accepted measures of health and vitality, or will only have an effect on health via some cryptic mechanism after the many years of use during which an individual is at typical risk for disease, is a tough sell.

Simply put, geroprotectors should provide overt health and disease prevention benefits but the time-dependent relationships between epigenetic clocks and health-related phenomena are complex and in need of further scrutiny. Therefore, studies that enable understanding of the relationships between epigenetic clocks and disease processes while simultaneously testing the efficacy of a candidate geroprotector are crucial to move the field forward.

When it comes to better maintaining the aging brain, understanding the creation of new neurons in adult life is an important topic. If there are processes by which new neurons arise and are integrated into the brain, then they are targets for therapies intended to increase that output. It is generally agreed upon that a greater supply of new neurons is a good thing, and may even enhance function at all ages, not just in later life. In that context, the discussion here, regarding a precursor cell population that is slowly used up over a lifetime in order to generate new neurons, is most interesting.

Dormant non-proliferative neuronal precursors (dormant precursors) are a unique type of undifferentiated neuron, found in the adult brain of several mammalian species, including humans. Dormant precursors are fundamentally different from canonical neurogenic-niche progenitors as they are generated exquisitely during the embryonic development and maintain a state of protracted postmitotic immaturity lasting up to several decades after birth. Thus, dormant precursors are not pluripotent progenitors, but to all effects extremely immature neurons. Recently, transgenic models allowed to reveal that with age virtually all dormant precursors progressively awaken, abandon the immature state, and become fully functional neurons.

Compelling evidence implies that dormant precursors in the adult brain are physiologically relevant and may contribute to an overlooked form of late brain maturation. Intriguingly, our brain seems to use this resource sparingly throughout the whole course of life. To fully understand the contribution of dormant precursors integration, it will be crucial to identify the molecular mechanisms promoting or hindering maturation and the behavioral impacts.

Considering the possibility of a precursor-based contribution to learning and adaptation of input processing in the young individuals may shed a new light on development. The handful of dormant precursors still available up to an advanced age may also constitute a precious resource and understanding the mechanisms that promote their late integration could allow to recover every last bit of untapped potential, perhaps improving cognition and/or adaptation in the aging brain. Importantly, the number of dormant precursors is inherently limited by their non-proliferative nature and purposely promoting their integration in early life will lead to their premature exhaustion. Therefore, a comprehensive understanding of the relevance of dormant precursors in processes of brain maturation and adaptation along the different life phases constitutes a pressing need.

Link: https://doi.org/10.3389/fnins.2022.877167

Visceral fat around the inner organs is a metabolically active tissue, and more of it is entirely detrimental to long-term health. These fat deposits interact with the immune system in a number of distinct ways to produce chronic inflammation, and that inflammation in turn drives the onset and progression of tissue dysfunction and all of the common age-related conditions. For example, visceral fat encourages the accumulation of senescent cells and their pro-inflammatory signaling, while visceral fat cells signal in ways that mimic infection, as well as producing DNA debris that activates the innate immune system. Given the number of known inflammatory processes, we might expect researchers to uncover further, novel mechanisms involved in generating inflammation in visceral fat, as is the case here.

γδ T cells are a unique and poorly understood class of lymphocytes generally regarded for their role in barrier protection with functionally distinct subpopulations residing in epithelial tissues, including those of the skin, gut, and lung. In addition to responding to antigen presentation via the T cell receptor, similar to conventional T cells (regulatory, helper, and cytotoxic T cells) of the adaptive immune system, γδ T cells can respond directly to cytokines and other intact proteins without antigen processing and presentation, and have the capacity to phagocytize much like innate immune cells.

In adipose tissues, contrary to their traditional function in infection control, γδ T cells appear to play major roles in maintaining homeostasis with respect to inflammation and insulin sensitivity. Adipose tissue γδ T cells have been shown to increase in number in mouse models of diet-induced obesity, where they promote macrophage accumulation, inflammation, and insulin resistance. More recently, they were reported to regulate adipose tissue regulatory T cell homeostasis and thermogenesis in adolescent and young-adult mice.

Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in visceral adipose tissue. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in visceral adipose tissue contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.

Link: https://doi.org/10.1007/s11357-022-00572-w

RNA splicing is the step in gene expression at which pieces of a gene are assembled into the final messenger RNA that encodes the resulting protein. A gene consists of intron sequences (omitted) and exon sequences (included). In some cases different combinations are produced normally and result in different proteins arising from the one gene. In other cases, such different combinations are entirely abnormal and should not occur in a healthy cell. With aging, breakages in the splicing process can result in the appearance of these broken proteins, or in changes in the normal balance of several different proteins produced from the same gene.

You might recall that SENISCA was founded to develop therapies based on reducing the age-related dysregulation of splicing that occurs in tissues throughout the body. The principals of that company argue for splicing dysregulation to be included among the hallmarks of aging, with the idea that it can produce much the same sort of disarray in gene expression as results from epigenetic dysregulation. One of the more interesting aspects of this work on correction of splicing is that it can reverse cellular senescence, in vitro. Accumulation of senescent cells is an important aspect of degenerative aging, and there appears to be a fairly deep connection between certain forms of splicing dysregulation and the onset and maintenance of cellular senescence.

Is it a good idea to restore senescent cells, however? Lorna Harris of SENISCA presented on her work at the recent Longevity Leaders World Congress conference, and the first audience question was exactly that. Yes, you can reverse senescence, but senescent cells are senescent for a reason, so is this restoration wise? Isn't it better to take the senolytic approach and destroy all of these errant cells? In answer, Harris explained her position as being that (a) the SENISCA therapeutics are only restoring cell cycle activity in cases of paracrine senescence, cells that are senescent because nearby senescent cells are encouraging them to adopt that state, and (b) the SENISCA therapeutics will not reverse senescence in profoundly damaged cells.

More data is needed to concretely back up that assertion, but it doesn't seem unreasonable. Not all senescent cells are identical in their regulation of the senescent state, and their state depends on cell type and mode of induction of senescence. That is not very controversial, but equally not very well mapped either. Setting aside the sketchy state of knowledge regarding variations between types of senescent cell, one possible reason to avoid reversal of paracrine senescence is the evidence to suggest that the process of becoming senescent produces significant nuclear DNA damage. Thus even undamaged cells may gain potentially problematic mutations when coerced into senescence by the signaling of other senescent cells.

At the end of the day, prospective risks involving cell damage and the prospect of cancer will have to be quantified with at least lengthy animal studies. That will no doubt happen here in the fullness of time, just as it will for many other approaches to treat age-related diseases by targeting hallmarks of aging.

It seems plausible that there is a roughly optimal human diet, a range within which one will age modestly more slowly than is the case when falling outside it. The work on fasting mimicking is quite solid, for example. What does one eat when not in a period of fasting mimicking, however? On this topic, the science tends to get drowned out by the marketing, ever a human failing. Given a more coordinated scientific community, it could be possible to produce data that is compelling, however, a reasonable and defensible answer to the question. Just don't expect that to turn up any time soon, or for it to settle the diet wars when it does.

Examining a range of nutrition research from studies in laboratory animals to epidemiological research in human populations provides a clearer picture of the best diet for a longer, healthier life. Researchers recently described the "longevity diet," a multi-pillar approach based on studies of various aspects of diet, from food composition and calorie intake to the length and frequency of fasting periods. The researchers reviewed hundreds of studies on nutrition, diseases, and longevity in laboratory animals and humans and combined them with their own studies on nutrients and aging.

The work also included a review of different forms of fasting, including a short-term diet that mimics the body's fasting response, intermittent fasting (frequent and short-term) and periodic fasting (two or more days of fasting or fasting-mimicking diets more than twice a month). In addition to examining lifespan data from epidemiological studies, the team linked these studies to specific dietary factors affecting several longevity-regulating genetic pathways shared by animals and humans that also affect markers for disease risk. These include levels of insulin, C-reactive protein, insulin-like growth factor 1, and cholesterol.

The authors report that the key characteristics of the optimal diet appear to be moderate to high carbohydrate intake from non-refined sources, low but sufficient protein from largely plant-based sources, and enough plant-based fats to provide about 30 percent of energy needs. Ideally, the day's meals would all occur within a window of 11-12 hours, allowing for a daily period of fasting. Additionally, a 5-day cycle of a fasting or fasting-mimicking diet every 3-4 months may also help reduce insulin resistance, blood pressure, and other risk factors for individuals with increased disease risks.

The next step in researching the longevity diet will be a 500-person study taking place in southern Italy. In addition to the general characteristics, the longevity diet should be adapted to individuals based on sex, age, health status, and genetics. For instance, people over age 65 may need to increase protein in order to counter frailty and loss of lean body mass.

Link: https://gero.usc.edu/2022/04/28/valter-longo-longevity-diet/

Philanthropist and investor Michael Greve directs funds into advocacy, research, and commercial development of SENS-like projects aimed at repair of underlying mechanisms of aging. His Forever Healthy Foundation undertakes a range of useful activities, such as reviewing existing therapies that may address aspects of aging, and running the Undoing Aging conference series. His venture fund, Kizoo, has invested in a range of biotech companies developing interventions for aging, most of which are in some way connected to the SENS outline for rejuvenation biotechnology.

Kizoo is investing €300 million in a portfolio of private science-backed biotechnology companies which are working to tackle age-related diseases. The funds underline Kizoo's commitment to these startups with the aim of advancing therapies from clinical development to patient. Startup projects include the decalcification of aged tissue, breaking of protein-glucose cross-links, and the delivery of new mitochondria to aged cells. These aim to prevent and repair age-related conditions such as myocardial infarction, stroke, high blood pressure, tissue stiffening, skin ageing, and loss of muscle function.

It's a grand proposition, but owner Michael Greve is very clear on his pursuit of these goals. "It's a personal thing for me. You can look after your lifestyle but eventually you come to realise you can't diet yourself healthy forever. Sooner or later you'll be susceptible to age-related diseases due to the ageing process. This is how I became interested in this field. Basically, all my entrepreneurial energy shifted to this area - rejuvenation biotech."

Greve acknowledges that globally there has been a significant shift to learn more about age-related diseases (ARDs) and that we have reached the point where we can keep them under medical control. Of course, ARD is a broad clinical area - anything from osteoporosis to some forms of cancer. Greve explains that there are two paradigms that are similar. One is the hallmarks of ageing and the other is the Strategies for Engineered Negligible Senescence (SENS) paradigm, which goes to the root of the issue. Greve and his team are working on the root causes to therefore prevent ARDs entirely.

Kizoo's strategy is to define this as a new sector in drug discovery. In order to drive this field, Kizoo makes what it calls 'lighthouse investments'. "These are part of our investment paradigm and are things that have never been done before but have the potential to become game-changers. We have several points that we want to prove with our investments. When we talk about age-related diseases and rejuvenation, many people think it's science fiction. We want to show this is not the case and that the reality of a pill or an injection to tackle the root cause is possible. We also want to demonstrate that it's going to be inexpensive and that the therapeutics will be for everybody. Finally, we want to make the public understand that what we are trying to do is uncomplicated."

Link: https://www.ddw-online.com/rejuvenation-biotech-can-this-company-make-age-a-thing-of-the-past-16744-202204/

Today's open access preprint paper touches on the important topic of synergy between therapies targeting mechanisms of aging. For a variety of reasons, far too little work in academia and industry is conducted on combinations of therapies, and not just for the treatment of aging. Intellectual property, bounds of domain knowledge, academic publishing incentives, and organizational inertia make it much harder to commit to the evaluation of two or more different therapies in combination than to focus only on one approach. This has always been the case in medical development, but it is a critical problem in the context of treating age-related disease by targeting the underlying mechanisms of aging. Aging has numerous distinct causes, and age-related diseases are the combined outcome of multiple distinct processes. Only limited benefits can be obtained by focusing on only one of those causes.

The end goal for the treatment of aging as a medical condition must be to address every important mechanism, employing a collection of therapies. In the early stages of the lengthy development process leading to that end goal, evaluation combinations of therapies will be an important part of optimizing ongoing allocation of time and resources. Yet next to no work is conducted on combination studies, and there is little prospect for an expansion of that work on the part of academia and industry, because of the established incentives. This may be a part of the field in which philanthropic ventures will have to do the heavy lifting. See, for example, the proposed later stages of the Astera Institute's Rejuvenome program.

Combining Stem Cell Rejuvenation and Senescence Targeting to Synergistically Extend Lifespan

Stem cells play a pivotal role in this tissue homeostasis by providing a reservoir of pluripotent precursor cells, needed to replace fully differentiated cells that are lost or damaged. At the opposite end of the cell-fate spectrum are senescent cells, or cells that have permanently withdrawn from the cell cycle. By entering permanent replicative arrest, senescent cells prevent mutations from expanding, thereby providing a sink for genotoxic damage. However, the senescent state does not simply result in passive replicative arrest but instead leads to transcriptional changes causing resistance to apoptosis and increased secretion of pro-inflammatory signaling molecules, a process known as Senescence Associated Secretory Phenotype (SASP). Senescent cell induced SASP in turn promotes inflammation and contributes to age-dependent dysfunction and to the development of age-related diseases.

While the number of stem cells decreases in aging animals, senescent cells accumulate with age. Manipulating cell fates by cellular reprogramming (to rejuvenate somatic cells) and by senolytic interventions (to remove senescent cells) are two promising approaches to restore homeostasis in aged individuals and to prevent age-dependent diseases.

Accumulation of senescent cells and loss of stem cells are not independent processes. Through SASP, senescent cells release large amounts of pro-inflammatory cytokines which contribute to chronic inflammation and mTOR activation, ultimately leading to stem cell exhaustion. This interaction suggests that senolytic therapies might interact with cellular reprogramming strategies in delaying age-dependent decline and disease. We have previously explored drug-drug interactions as synergistic aging interventions, and here we ask whether a combinatorial treatment of the Yamanaka factors (OKSM) and senolytic (Sen) expression could mitigate or reverse the effects of aging more efficiently than either intervention alone. To test this hypothesis, we induced expression of OKSM, Sen and an OKSM-Sen combination in adult flies and compared their effects on health and lifespan.

We find that each treatment alone had limited benefits, with OKSM alone benefiting maximum lifespan at the expense of healthspan while Sen expression alone increased mean lifespan but had no effect on maximum lifespan. In contrast, animals subjected to the combined intervention experienced substantially longer mean and maximum lifespan. Our data is consistent with a synergistic interaction between the two interventions, simultaneously rejuvenating stem cells and removing senescent cells.

The gut microbiome changes with age in ways that provoke greater chronic inflammation in the body, as well as reducing the production of beneficial metabolites, such as those that influence neurogenesis. When thinking about stroke resulting from the progression of atherosclerosis and hypertension, inflammation is an important factor, but there are other mechanisms that might link the aging of the gut microbiome and the aging of the vasculature in the brain. Some of these connections are discussed in the open access review paper noted here.

The microbiota-gut-brain-axis (MGBA) is a bidirectional communication network between gut microbes and their host. Many environmental and host-related factors affect the gut microbiota. Dysbiosis is defined as compositional and functional alterations of the gut microbiota that contribute to the pathogenesis, progression and treatment responses to disease. Dysbiosis occurs when perturbations of microbiota composition and function exceed the ability of microbiota and its host to restore a symbiotic state. Dysbiosis leads to dysfunctional signaling of the MGBA, which regulates the development and the function of the host's immune, metabolic, and nervous systems.

Dysbiosis-induced dysfunction of the MGBA is seen with aging and stroke, and is linked to the development of common stroke risk factors such as obesity, diabetes, and atherosclerosis. Changes in the gut microbiota are also seen in response to stroke, and may impair recovery after injury. In this review relevant MGBA components are introduced and summarized for a better understanding of age-related changes in MGBA signaling and its dysfunction after stroke. We will then focus on the relationship between the MGBA and aging, highlighting that all components of the MGBA undergo age-related alterations that can be influenced by or even driven by the gut microbiota.

In the final section, the current clinical and preclinical evidence for the role of MGBA signaling in the development of stroke risk factors such as obesity, diabetes, hypertension, and frailty are summarized, as well as microbiota changes with stroke in experimental and clinical populations. We conclude by describing the current understanding of microbiota-based therapies for stroke including the use of prebiotics/probiotics and supplementations with bacterial metabolites. Ongoing progress in this new frontier of biomedical sciences will lead to an improved understanding of the MGBA's impact on human health and disease.

Link: https://doi.org/10.1161/CIRCRESAHA.122.319983

While much of the focus on cell reprogramming these days is upon the ability of reprogramming factors to produce epigenetic and functional rejuvenation, there are other lines of research. Here, researchers show that short-term exposure to reprogramming factors can improve liver regeneration in mice. This is interesting, but as noted the liver is a very regenerative organ in comparison to other mammalian tissues, and the mechanisms of regeneration may be distinct from other tissues. Thus the ability to improve regeneration in the liver via reprogramming may or may not generalize to other organs.

Researchers previously showed how four cellular reprogramming molecules Oct-3/4, Sox2, Klf4, and c-Myc, also called "Yamanaka factors", can slow down the aging process as well as improve muscle tissue regeneration capacity in mice. In their latest study, the authors used Yamanaka factors to see if they could increase liver size and improve liver function while extending the health span of the mice. The process involves partially converting mature liver cells back to "younger" states, which promotes cell growth.

The issue many researchers in the field face is how to control the expression of factors needed for improving cell function and rejuvenation as some of these molecules can cause rampant cell growth, such as occurs in cancer. To circumvent this, researchers used a short-term Yamanaka factor protocol, where the mice had their treatment administered for only one day. The team then tracked the activity of the partially reprogrammed liver cells by taking periodic samples and closely monitoring how cells divided over several generations. Even after nine months - roughly a third of the animal's life span - none of the mice had tumors.

"Yamanaka factors are truly a double-edged sword. On the one hand, they have the potential to enhance liver regeneration in damaged tissue, but the downside is that they can cause tumors. We were excited to find that our short-term induction protocol has the good effects without the bad-improved regeneration and no cancer."

Link: https://www.salk.edu/news-release/cellular-regeneration-therapy-restores-damaged-liver-tissue-faster-than-ever/

A range of data on the benefits produced by simple health interventions in late life suggests that many people are self-sabotaging to a point at which a significant fraction of age-related disease and mortality might be legitimately thought of as being self-inflicted. To pick one example, if programs of moderate exercise improve health and reduce mortality in old people, which they do, then the conclusion must be that older people are harming themselves by not undertaking sufficient exercise.

Cancer is one of the more important classes of age-related condition. It is age-related for a range of reasons, such as rising levels of chronic inflammation that make the tissue environment more hospitable to cancerous growth, and the progressive failure of the immune system to identify and destroy pre-cancerous and cancerous cells at the earliest stages. If people adopt better lifestyle choices or other simple interventions that reduce these and other issues, then how much of cancer might be avoided? Today's open access paper reports on study results suggesting the answer to that question is perhaps a larger fraction than one might have thought.

A combination of three simple treatments may reduce invasive cancer risk by 61% among adults aged 70+

Mechanistic studies have shown that vitamin D inhibits the growth of cancer cells. Similarly, omega-3 may inhibit the transformation of normal cells into cancer cells, and exercise has been shown to improve immune function and decrease inflammation, which may help in the prevention of cancer. However, there was a lack of robust clinical studies proving the effectiveness of these three simple interventions, alone or combined.

Researchers conducted the DO-HEALTH trial: a three-year trial in five European countries (Switzerland, France, Germany, Austria, and Portugal) with 2,157 participants. The results show that all three treatments, vitamin D3, omega-3s, and simple home strength exercise program (SHEP), had cumulative benefits on the risk of invasive cancers. Each of the treatments had a small individual benefit but when all three treatments were combined, the benefits became statistically significant, and the researchers saw an overall reduction in cancer risk by 61%.

Combined Vitamin D, Omega-3 Fatty Acids, and a Simple Home Exercise Program May Reduce Cancer Risk Among Active Adults Aged 70 and Older: A Randomized Clinical Trial

Generally healthy community-dwelling adults ≥70 years were recruited. The intervention was supplemental 2000 IU/day of vitamin D3, and/or 1 g/day of marine omega-3s, and/or a simple home strength exercise (SHEP) programme compared to placebo and control exercise. In total, 2,157 participants (mean age 74.9 years; 61.7% women; 40.7% with 25-OH vitamin D below 20 /ml, 83% at least moderately physically active) were randomized.

Over a median follow-up of 2.99 years, 81 invasive cancer cases were diagnosed and verified. For the three individual treatments, the adjusted hazard ratios (HRs) were 0.76 for vitamin D3, 0.70 for omega-3s, and 0.74 for SHEP. For combinations of two treatments, adjusted HRs were 0.53 for omega-3s plus vitamin D3; 0.56 for vitamin D3 plus SHEP; and 0.52 for omega-3s plus SHEP. For all three treatments combined, the adjusted HR was 0.39.

You might recall that researchers recently demonstrated that vaccination against GPNMB is a senolytic strategy, reducing the harmful burden of senescent cells in aged tissues by directing the immune system to destroy these cells. Here the same team reports on their further investigation of the role of GPNMB in senescent cells. Why is GPNMB expression upregulated in senescent cells to the point of it being a good target for immune based senolytic therapies? The answer appears to be that it is protective against certain forms of stress inherent in the state of cellular senescence.

Accumulation of senescent cells in various tissues has been reported to have a pathological role in age-associated diseases. Elimination of senescent cells (senolysis) was recently reported to reversibly improve pathological aging phenotypes without increasing rates of cancer. We previously identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as a seno-antigen specifically expressed by senescent human vascular endothelial cells and demonstrated that vaccination against Gpnmb eliminated Gpnmb-positive senescent cells, leading to an improvement of age-associated pathologies in mice.

The aim of this study was to elucidate whether GPNMB plays a role in senescent cells. We examined the potential role of GPNMB in senescent cells by testing the effects of GPNMB depletion and overexpression in vitro and in vivo. Depletion of GPNMB from human vascular endothelial cells shortened their replicative lifespan and increased the expression of negative cell cycle regulators. Conversely, GPNMB overexpression protected these cells against stress-induced premature senescence. Depletion of Gpnmb led to impairment of vascular function and enhanced atherogenesis in mice, whereas overexpression attenuated dietary vascular dysfunction and atherogenesis.

In conclusion, our results taken together with the above considerations demonstrated that GPNMB was upregulated by lysosomal stress associated with cellular senescence and acted as a protective factor for senescent cells, and suggest that targeting cell/tissue-specific seno-antigens like GPNMB could be a reasonable strategy for next-generation senolytic therapy with higher selectivity and fewer off-target effects.

Link: https://doi.org/10.1038/s41598-022-10522-3

Researchers here report on a study of transplantation of bone marrow from young mice to old mice, showing that it improves some measures of immune function, but fails to extend life span. One can compare this with a study from a few years back in which the same approach did in fact extend remaining life span in the old mice. Failures of this nature, where one would expect there to be benefits, are a challenge, as it remains the case that we expect benefits to result if the process was only better optimized in some way. It is hard to draw the line and say that a particular implementation will not work, and why it will not work, without a great deal of further work.

The stem cell theory of aging postulates that stem cells become inefficient at maintaining the original functions of the tissues. We, therefore, hypothesized that transplanting young bone marrow (BM) to old recipients would lead to rejuvenating effects on immunity, followed by improved general health, decreased frailty, and possibly life span extension. We developed a murine model of non-myeloablative heterochronic BM transplantation in which old female BALB/c mice at 14, 16, and 18(19) months of age received altogether 125.1 ± 15.6 million nucleated BM cells from young male donors aged 7-13 weeks. At 21 months, donor chimerism was determined, and the immune system's innate and adaptive arms were analyzed. Mice were then observed for general health and frailty until spontaneous death, when their lifespan, post-mortem examinations, and histopathological changes were recorded.

The results showed that the old mice developed on average 18.7 ± 9.6% donor chimerism in the BM and showed certain improvements in their innate and adaptive arms of the immune system, such as favorable counts of neutrophils in the spleen and BM, central memory Th cells, effector/effector memory Th and Tc cells in the spleen, and B1a and B1b cells in the peritoneal cavity. Borderline enhanced lymphocyte proliferation capacity was also seen. The frailty parameters, pathomorphological results, and life spans did not differ significantly in the transplanted vs. control group of mice. In conclusion, although several favorable effects are obtained in our heterochronic non-myeloablative transplantation model, additional optimization is needed for better rejuvenation effects.

Link: https://doi.org/10.3390/biom12040595

Cellular senescence is now well recognized as an important contributing cause of fibrosis, a malfunction of normal tissue maintenance that involves deposition of excess collagen into scar-like structures that degrade tissue function. Pulmonary fibrosis is one of the better studied age-related fibrotic conditions, and over the past decade it has been increasingly linked to cellular senescence. Some of the first clinical trials of senolytic drugs to clear senescent cells, using the dasatinib and quercetin combination, were carried out in patients with idiopathic pulmonary fibrosis.

Senescent cells cause harms, such as the disruption of regenerative processes that leads to fibrosis, via the signals that they generate, the pro-inflammatory, pro-growth senescence-associated secretory phenotype (SASP). How exactly does the SASP produce fibrosis, however? Today's open access paper is an example of the research initiatives presently attempting to answer that question. The focus here is on the production of excess fibroblasts, cells that produce the collagen structures of the extracellular matrix, in the context of fibrosis, and the mechanisms by which this happens.

Endothelial Cell Senescence Exacerbates Pulmonary Fibrosis Potentially Through Accelerated Endothelial to Mesenchymal Transition (PDF)

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by progressive lung fibrosis and obliteration of normal alveolar structures. Myofibroblasts play a central role in the progression of IPF by producing excess amount of extracellular matrix, and these myofibroblasts show heterogenous origins including resident fibroblasts, epithelial cells via epithelial to mesenchymal transition (EMT) and endothelial cell (EC) via endothelial to mesenchymal transition (EndMT).

Although lung aging has been considered as essential mechanisms through abnormal activation of epithelial cells and fibroblasts, little is known about a role of EC senescence in the pathogenesis of IPF. Here, we reveal a detrimental role of EC senescence in IPF by utilizing unique EC-specific progeroid mice. EC-specific progeroid mice showed deteriorated pulmonary fibrosis in association with an accelerated EndMT in the lungs after intratracheal bleomycin instillation. We further confirmed that premature senescent ECs were susceptible to EndMT in vitro. Because senescent cells affect nearby cells through senescence-associated secretory phenotype (SASP), we assessed a potential role of the EC-SASP in EMT and myofibroblastic transition of resident fibroblasts. EC-SASP enhanced the myofibroblastic transition in resident fibroblasts, while no effect was detected on EMT.

Our data revealed a previously unknown role of EC senescence in the progression of IPF, and thus rejuvenating ECs and/or inhibiting EC-SASP is an attracting therapeutic strategy for the treatment of IPF.

The accumulation of altered tau protein, forming harmful aggregates, is a feature of a number of age-related neurodegenerative conditions, classed as tauopathies. This interesting paper discusses the evidence for tauopathies to be associated with an increased burden of double strand breaks, a form of DNA damage. Such damage is disruptive if prevalent, and recent evidence suggests that even repaired double strand breaks alter cell epigenetics in ways that encourage age-related declines in cell function. The researchers here suggest a bidirectional relationship, with tau pathology both degrading DNA repair mechanisms, and being driven by DNA damage.

DNA double-strand break (DSB) is the most severe form of DNA damage and accumulates with age, in which cytoskeletal proteins are polymerized to repair DSB in dividing cells. Since tau is a microtubule-associated protein, we investigate whether DSB is involved in tau pathologies in Alzheimer's disease (AD). First, immunohistochemistry reveals the frequent coexistence of DSB and phosphorylated tau (p-tau) in the cortex of AD patients. In vitro studies using primary mouse cortical neurons show that non-p-tau accumulates perinuclearly together with the tubulin after DSB induction with etoposide, followed by the accumulation of phosphorylated tau. Moreover, the knockdown of endogenous tau exacerbates DSB in neurons, suggesting the protective role of tau on DNA repair.

Interestingly, synergistic exposure of neurons to microtubule disassembly and the DSB strikingly augments aberrant p-tau aggregation and apoptosis. These data suggest that DSB plays a pivotal role in AD-tau pathology and that the failure of DSB repair leads to tauopathy.

In summary, neurons are physiologically exposed to various crises, such as aging, oxidative stress, genetic mutation, and excitotoxicity, all of which cause DNA damage. Under normal conditions, when DNA damage occurs, cytoskeletal proteins, such as microtubules, polymerize to execute DNA repair, and they might form a link with the nuclear membrane for the repair. Tau may well be involved in the rearrangement of microtubules to assist this process. However, the excessive DNA damage may cause accumulation of p-tau and may disassemble microtubules, which may exacerbate DNA damage and lead to neuronal cell death.

Link: https://doi.org/10.1038/s42003-022-03312-0

Levels of nicotinamide adenine dinucleotide (NAD) are relevant to mitochondrial function and decline with age for reasons that are only partially explored. Proximate causes are well outlined, the faltering of salvage and synthesis pathways due to lower levels of necessary molecules, but the connections to deeper causes of aging remain to be mapped. When it comes to NAD+ upregulation via vitamin B3 derivatives, boosting the operation of those pathways, there is more human data for nicotinamide riboside (NR) than for nicotinamide mononucleotide (NMN), so it is interesting to see the trial data here. It remains a question as to whether approaches that upregulate NAD are worth pursuing, given that they don't appear be any better than regular exercise programs at raising NAD levels, and the clinical trial data that assessed actual benefits to patients is very mixed.

It has been widely reported that mammalian intracellular NAD levels decrease significantly during aging and the decline has profound impact on aging related health issues. β-Nicotinamide mononucleotide (NMN) supplementation as a precursor to boost intracellular NAD has proven highly effective and safe in many animal studies. However, only limited number of human clinical trials have been done on NMN.

This randomized, multicenter, double-blind, placebo-controlled, parallel-group, dose-dependent human clinical trial was done at two clinical centers in Pune, India. 84 healthy middle-aged and older adults (40 - 65 years old) of both males and females were screened. 80 were recruited, randomized, and stratified in 1:1:1:1 ratio for a 60-day clinical study with once daily oral dosing of placebo, 300mg, 600mg, and 900mg NMN which were dispensed and monitored by principal investigators at the clinical centers.

Blood intracellular NAD levels were found statistically significantly increased among all NMN treated groups. The mean percentage increases of blood cellular NAD levels over baselines at day 30 were 21.20%, 151.70%, 390.70%, and 312.82% for placebo, 300mg, 600mg, and 900mg respectively while at day 60, the increases were 45.10%, 175.80%, 470.30%, and 364.31% for placebo, 300mg, 600mg, and 900mg respectively. The similar results were observed with the distances in six-minute walking test for physical endurance assessment. The mean percentage increases of the distance walked in six minutes over baselines were -4.56%, 13.88%, 38.10%, and 31.48% at day 30 and 1.60%, 23.64%, 50.18%, and 48.4% at day 60 for placebo, 300mg, 600mg, and 900mg respectively.

Link: https://doi.org/10.2139/ssrn.4081081

Compression of morbidity is a reduction in the length of time spent in significant illness or disability at the end of life. It is often touted as a goal in human medicine by those who, for various reasons, don't want to talk about the prospects for extending overall life span through progress in medicine. If we think about aging in terms of damage to a machine, then in the simple model of a single form of damage, compression of morbidity would not be expected to occur in response to a slowed accumulation of damage. Fully functional life span would extend, but so would the period of progressive onset of dysfunction.

Humans are machines, albeit very complicated machines. There is some debate over whether compression of morbidity in humans is possible to achieve, or happening at present as a result of improvements in public health and medical technology, in the context of overall life expectancy slowly increasing year over year. This is one of many areas of epidemiology in which data can be assembled to support almost any view of the situation, while definitions and what is actually being measured make a big difference, particularly the specifics of what is meant by "morbidity" in late life.

The roots of aging consist of a number of different forms of molecular damage. They do interact with one another, and tend to make one another worse, accumulating more rapidly as damage grows, but is possible to envisage a situation in which some forms of damage (a) are less influenced than others by public health measures or medical technology, and (b) only produce very significant mortality very late in life. This may or may not in fact be the case, but the accumulation of transthyretin amyloid in the cardiovascular system with age is a possible candidate. It does appear to influence mortality in younger old age, but there is evidence for it to be the majority cause of death in supercentenarians. In this scenario, therapies to treat aging that failed to change the burden of transthyretin amyloid would tend to produce compression of morbidity.

In today's open access paper, researchers note an absence of compression of morbidity in nematode worms subject to longevity-inducing mutations. This change in metabolism lengthens the period of healthy life span but also lengthens the period of disability in proportion - which is akin to the simple model of a damaged mechanism mentioned above. This work is also an example of the importance of details when it comes to the assessment of morbidity; the paper is in a part a discussion of a novel means for determining whether an old nematode is in fact decrepit, with the implication that earlier studies were not assessing degeneration well enough or in a relevant way.

Longevity interventions temporally scale healthspan in Caenorhabditis elegans

The continuously growing elderly population is projected to result in 1.5 billion people older than 65 years globally by 2050. This poses a significant challenge, as old age is the major risk factor for developing cancer, dementia, cardiovascular, and metabolic diseases, especially because people suffer for approximately 20% of their lifespan from one or multiple of these chronic illnesses, which are themselves accompanied by other late-life disabilities. Current estimates indicate that delaying the onset of these chronic diseases by one year would save $38 trillion in the US alone. Therefore, major research efforts are dedicated to understanding how to increase the time spent in good health (i.e., healthspan) and to postpone and compress the time spent suffering from age-related pathologies and chronic diseases (i.e., sickspan).

Mutations in genes that promote longevity in model organisms, such as Caenorhabditis elegans, have been instrumental in identifying mechanisms that promote healthy aging. A recent study has questioned this approach of using C. elegans longevity mutants to gain insights for promoting healthy aging or mechanisms that prolong healthspan. Using four matrices (resilience to heat and oxidative stress, voluntary movement, and swimming performance) to assess the "health" status of aging C. elegans, they found that four commonly used longevity mutants outperformed wild type at any given time point at older ages, consistent with previous reports. However, compared with their maximum lifespan, longevity mutants displayed an increased sickspan-to-healthspan ratio compared with wild type. Other studies have not observed an increase of sickspan in long-lived C. elegans mutants, except in the case of lower mobility or movement scores for the insulin/IGF-1 receptor longevity daf-2 mutants.

Although all these studies showed that sickspan is not increased in longevity mutants, the question remained about how healthspan changes when the lifespan is extended. We hypothesized that using other health matrices independent of voluntary or behavioral influences, such as physical properties of muscular strength, which is one of the best predictors for all-cause mortality in humans, we might be able to quantify the health trajectory of C. elegans longevity mutants.

Here we confirm that voluntary movement during aging declines, and this fragility is not extended in longevity mutants, except mildly in daf-2 mutants, using high-resolution lifespan and movement measurements on plates. We developed a novel microfluidic device and applied acoustophoretic force fields to quantify the maximum force and power of C. elegans. Using a high-frequency and high-power acoustic force field, it becomes possible to set up a contactless, constant in time, and uniform force field acting along the whole C. elegans body. Therefore, this force field challenges swimming C. elegans in a similar way body-weight exercises do for humans in a gravity field. Furthermore, applying the acoustic field stimulated a swimming response of resting C. elegans. All longevity mutants showed delayed onset of the decline in maximum force and dynamic power during aging. We observed heterogeneity between individuals across all genotypes in the onset of age-related phenotypes, several correlated phenotypes, and a time-dependent occurrence of multiple disabilities. However, we did not find a compression of sickspan but rather a temporal scaling of healthspan relative to their maximal lifespan across genotypes.

Age-related deafness is caused by some mix of loss of sensory hair cells of the inner ear, and loss of connections between those cells and the brain. A range of potential approaches to restore those cells are under development, and the work here is an example of this sort of work. Researchers have constructed an AAV viral vector that has some specificity for hair cells and nearby supporting cells, and which can be used to deliver a gene therapy payload that converts those supporting cells into new hair cells.

Cells of the cochlea, such as hair cells (HCs) and supporting cells (SCs), are essential for hearing. While sensorineural hearing loss can result from genetic mutations in both HCs and SCs, non-genetic stresses, such as noise, ototoxic medicines, or aging, can also induce deafness through damaging HCs. In either case, these damages are irreversible in mammals who do not have the ability to regenerate cochlear cells. Notably, SCs have the potential to transdifferentiate into HC-like cells.

Gene therapies have emerged as important treatments for genetic diseases, and current progress also demonstrates their potential for treating hearing loss. Several genes, such as tmc1, clrn, and otof, when being delivered to cochleae, can restore hearing function in animal models. Adeno-associated viruses (AAVs) have been shown to possess high safety in both animal models and humans. Previously, we developed a synthetic AAV, AAV-ie, which targets SCs and HCs. AAV-ie can regenerate HC-like cells through delivering the transcription factor, Atoh1, which transdifferentiates SCs into HC-like cells. However, its targeting efficiencies for SCs or HCs need to be improved, especially in the basal region of cochleae.

In the present study, we performed mutational screening on the AAV-ie capsid. We generated a repertoire of mutants on the amino acid sequence of AAV-ie capsids to manipulate phosphorylation/ubiquitination of AAVs in cells. We demonstrated that a particular amino acid-mutant AAV-ie capsid, AAV-ie-K558R, can transduce SCs with high efficiency and is suitable for correcting dysfunctional genetic mutations or for HC-like regeneration.

Link: https://doi.org/10.1038/s41392-022-00938-8

Research community is interested in the production of therapies to treat aging and age-related conditions based on partial reprogramming, exposing somatic cells to the Yamanaka factors for long enough to produce a rejuvenation of epigenetic patterns, but not long enough to change cell state. Reprogramming comes with an attendant risk of cancer, and reprogramming shares at least some molecular commonalities with the biochemistry of cancer cells, apparently enough so that the immune system will step in. The data presented in this paper supports a role for natural killer cells in destroying cells that are undergoing in vivo reprogramming. Evidently, this isn't enough to prevent benefits from occurring in past animal studies of reprogramming, but it may be a hurdle on the way to producing therapies for human patients.

The ectopic expression of the transcription factors OCT4, SOX2, KLF4, and MYC (Yamanaka factors, OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. However, little is known about the barriers that impair reprogramming in an in vivo context.

We report that natural killer (NK) cells significantly limit reprogramming, both in vitro and in vivo. Cells and tissues in the intermediate states of reprogramming upregulate the expression of NK-activating ligands, such as MULT1 and ICAM1. NK cells recognize and kill partially reprogrammed cells in a degranulation-dependent manner. Importantly, in vivo partial reprogramming is strongly reduced by adoptive transfer of NK cells, whereas it is significantly increased by their depletion. Notably, in the absence of NK cells, the pancreatic organoids derived from OSKM-expressing mice are remarkably large, suggesting that ablating NK surveillance favours the acquisition of progenitor-like properties.

We conclude that NK cells pose an important barrier for in vivo reprogramming, and speculate that this concept may apply to other contexts of transient cellular plasticity.

Link: https://doi.org/10.1242/dev.200361