Fight Aging!

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/

Longevity Industry Consulting Services

Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/

Contents

• Probiotics versus Neuroinflammation and Its Consequences
• A Conservative View of Aging Research and Development of Treatments Targeting Mechanisms of Aging
• The Atrophy of Lymph Nodes with Age Negatively Impacts Immune Function
• What To Do About the Aging of the Glymphatic System?
• A Look Back at 2022: Progress Towards the Treatment of Aging as a Medical Condition
• Progress Towards Decoupling Epigenetic Rejuvenation from Cell Identity Change in Partial Reprogramming
• Monocytes Become More Inflammatory with Age
• MERTK Inhibition Increases Bone Density via Increased Osteoblast Activity
• eIF2α as a Target to Prevent T Cell Stress and Loss of Function in Cancer Immunotherapy
• Notes on the 2022 Longevity Summit at the Buck Institute
• Angiotensin II Increases Oxidative Stress in Aging
• A Popular Science View of the Development of Senolytic Therapies
• The SenNet Consortium Intends to Map Senescent Cells Throughout the Human Lifespan
• A Circular RNA Regulates SYP Expression to Improve Memory Function in Mice
• Senescent Cells Inhibit Muscle Stem Cell Function and Regenerative Capacity

Probiotics versus Neuroinflammation and Its Consequences
https://www.fightaging.org/archives/2022/12/probiotics-versus-neuroinflammation-and-its-consequences/

The balance of microbial populations making up the gut microbiome is now known to change with age in ways that promote chronic inflammation. There are more inflammatory microbes passing the intestinal barrier to enter tissue, and more microbes capable of generating harmful metabolites that aggravate cells. The aging of the microbiome is only loosely connected to the aging of the body, however. Animal studies make it clear that the gut microbiome of an old individual can be restored to a youthful balance of populations via fecal microbiota transplant from a young individual, benefits to health and longevity result, and that one intervention lasts for a long time.

It is in principle possible to achieve the same result as a fecal microbiota transplant using probiotics, given a large enough sustained dose. In practice, that cannot yet be accomplished, however. The right balance of species would have to be manufactured, and present probiotic manufacture is limited to a very small number of microbial species in comparison to what one finds in the gut microbiome.

Even given the point that one or two of the species known to lose abundance with age might be capable of delivering enough of a benefit to be worth it, even if only a fraction of that produced by fecal microbiota transplant, the actual result of present probiotic treatment, the products one can purchase in a store, appears to be at best a comparatively small, short-lived benefit. Still, given what is presently known of the impact of the gut microbiome on health, and how to rejuvenation an aged gut microbiome, it seems likely that probiotics will become a good deal better in the years ahead.

Can probiotics mitigate age-related neuroinflammation leading to improved cognitive outcomes?

Systemic inflammation, which leads to neuroinflammation, is likely a risk factor for the progression of neurodegenerative diseases. Although systemic inflammation can be the result of numerous processes and diseases, one key trigger during aging is changes in the gut, such as the increase in gut permeability and alterations in microbiota composition. During aging, the gut naturally becomes more permeable. The gastrointestinal tract is the second largest interface between the host and the outside world. Therefore, this reduction in its barrier function associated with aging has follow-on consequences, such as allowing unwanted components (antigens and opportunistic pathogenic bacteria) to enter the body, leading to the production of proinflammatory cytokines in the blood. These cytokines can then cross the blood brain barrier to cause neuroinflammation, which impacts brain function.

Whether age-associated increases in gut permeability are a cause or a consequence of other gut related changes is currently unknown. However, a recent study showed that the development of gut barrier dysfunction during aging is not consistent across all people. People with irritable bowel syndrome (IBS) are more susceptible to gut hyperpermeability in later life than healthy individuals. Interestingly, those with IBS are also more at risk at developing Alzheimer's disease (AD), supporting the idea that gut hyperpermeability is a risk factor for AD.

Recent studies have sought to define a microbiota profile associated with healthy aging, but this varies between the study populations. However, gut microbiota composition of people with AD has been shown to differ from that of healthy older adults in a number of studies. Recent studies have also shown there is a difference in the composition of the gut microbiota between people with mild cognitive impairment (MCI) and those without, and that these differences are similar to those seen in people with AD. This implies that microbiota dysbiosis proceeds AD development and, therefore, may be a driver in the disease progression.

It therefore follows that treatments that can maintain healthy gut function may reduce inflammation and protect against, or improve, symptoms of age-associated neurodegeneration. The aim of this mini-review was to evaluate whether probiotics could be used for this purpose. A search resulted in 187 papers describing primary research on probiotic intervention with older adults. A review of this research concluded that there is preliminary evidence to suggest that specific probiotics may improve cognitive function, particularly in those with MCI; however, this is not yet convincing and larger, multilocation, studies focus on the effects of probiotics alone are required. In addition, studies that combine assessment of cognition alongside analysis of inflammatory biomarkers and gut function are needed. Immense gains could be made to the quality of life of the aging population should the hypothesis be proven to be correct.

A Conservative View of Aging Research and Development of Treatments Targeting Mechanisms of Aging
https://www.fightaging.org/archives/2022/12/a-conservative-view-of-aging-research-and-development-of-treatments-targeting-mechanisms-of-aging/

A present, the conservative scientific viewpoint on aging is that significant progress has been made in understanding how to produce therapies that might target mechanisms of aging, but these are still very early days in both (a) understanding in detail how those mechanisms give rise to the observed outcomes in aging, and (b) the development of age-slowing and rejuvenating therapies. It is most likely the case that more could be accomplished than is presently being accomplished, given greater will and funding. But the creation of a new field of medicine is a slow process, proceeding incrementally, taking years to convince each new larger and more conservative audience of the merits of the work.

A small number of people were convinced by the SENS proposals for rejuvenation biotechnology twenty years ago, which included a synthesis of the evidence for senescent cells to contribute to degenerative aging. A larger group of people were convinced a decade ago by concrete demonstrations in which clearing senescent cells produced rejuvenation in mice. Since then, bootstrapping of a longevity industry and a greater focus on aging in the research community has proceeded, but the largest and most conservative groups still remain to be convinced. The majority of decision makers in the pharmaceutical industry won't act on the potential for the treatment of aging until a fair number of therapies are approved by regulators, find a large market, and are proven useful in humans, for example.

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

Research on the mechanisms of aging is a very active area in academia and a difficult area of research in the biomedical field. The study of aging mechanisms will be extremely important for delaying aging, reducing the occurrence of aging-related diseases, and maintaining a long and healthy life in human body. Especially, in recent years, research on epigenetic regulation, proteostasis, autophagy, cellular senescence, stem cell, has provided us with new directions for aging mechanism study. However, the causes of human aging are multifaceted, and the mechanisms of aging are extremely complex.

So far, although a variety of theories on the mechanism of aging have been proposed by academics, all of which have their own experimental basis, but they all have their limitations to explain the complex mechanisms of aging. Therefore, we should adopt a comprehensive and multi-perspective approach when we explain the aging mechanisms. At present, there has been great progress in the research on the molecular mechanisms of aging, and there has been a breakthrough in the understanding of the biological and genetic mechanisms of the aging process, as well as a profound understanding of the pathogenesis of aging-related diseases. However, these findings are still far from being able to delay human aging and reduce the occurrence of aging-related diseases. Therefore, there is still a long way to go in the study of aging mechanisms.

Antiaging interventions and treatments for aging-related diseases face great challenges. An important way to achieve healthy aging is through early intervention and prevention. Early lifestyle intervention can promote healthy longevity and reduce aging-related diseases. Through a variety of lifestyle interventions, it is hoped that the aging process can be slowed and the incidence of aging-related diseases may be reduced. In terms of pharmacological interventions and treatments for aging-related diseases, most of the drugs now applied clinically may focus more on symptom relief after the onset of disease and lack therapeutic approaches to address the causes of aging and aging-related diseases. Research on the latest therapeutic approaches, such as stem cell transplantation, elimination of senescent cells, promotion of antiaging factor expression and inhibition of pro-aging factor expression, and tissue or organ regeneration, provides new directions for treatments of aging-related diseases. In addition, there have been significant technological developments, mainly through gene therapy, nanomaterial drug carriers, therapeutic antibodies, or small molecule drugs, which have also contributed to advances in the treatment of aging-related diseases. Some of these methods and technologies have been applied in the clinic, and some are undergoing model animal studies and small-scale clinical studies. The application of these state-of-the-art technological approaches and new targeted drugs will facilitate the treatment and clinical application of aging-related diseases.

The goal of aging medicine is gradually changing from disease treatment to prevention of the occurrence and development of aging-related diseases. In other words, geriatric medicine is moving away from focusing on postdisease treatment to targeting aging-related chronic disease risk factors for preintervention. Research on the mechanisms of aging and on intervention measures and methods has an important role in improving human health and prolonging lifespan. Due to the aging of the global population, antiaging and healthy aging pursuits are undoubtedly important tasks for public health organizations, scientific research departments and drug research and development departments. Although there are many challenges to the research of aging and aging-related diseases and many questions still need to be addressed, promoting healthy aging has important and far-reaching socioeconomic and public health implications. With the emergence of new technologies and methods of modern biology, and the development and utilization of new drug discovery methods, research on aging mechanisms will further facilitate the prevention, diagnosis, and treatment of aging-related diseases, thus promoting healthy longevity for humans.

The Atrophy of Lymph Nodes with Age Negatively Impacts Immune Function
https://www.fightaging.org/archives/2022/12/the-atrophy-of-lymph-nodes-with-age-negatively-impacts-immune-function/

The lymphatic system allows rapid transit of large numbers of immune cells throughout the body. Scattered through this system of lymphatic vessels are the lymph nodes. Lymph nodes are vital to the function of the immune system, acting as meeting places where immune cells can communicate to effectively coordinate the response to pathogens. With age, lymph node structure begins to break down, however, becoming fibrotic, or the active tissue replaced by fat. Researchers have shown that this is an obstacle to rejuvenation of the adaptive immune system; one can regrow the atrophied thymus to provide a supply of new T cells, but without a fully functioning lymphatic system, the immune response is not properly coordinated.

Replacement of lymph nodes is a possibility, and it has been demonstrated that suitable organoids or other structures will produce new lymph nodes when implanted into the body. It is an open question as to whether this would work well in older individuals, in an aged tissue environment, however. Forms of regenerative therapy based on adjusting the signals controlling growth in lymphatic tissue, analogous to the approaches that can be used to regrow an atrophied thymus in animal studies, may be the better way forward. Little work has taken place in this part of the field, however. It is only comparatively recently that a broader recognition of the importance of lymph node aging has emerged.

How fat takes over the lymph nodes as we age

As we age, the normal tissue in the lymph nodes (the stroma) is gradually replaced by adipose tissue (fat). The phenomenon is known as lymph node lipomatosis. Although lipomatosis is very common and increases with age, researchers have previously devoted very little discussion and research to it. By careful analysis of more than 200 lymph nodes, researchers have demonstrated that lipomatosis begins in the central part of the lymph node, known as the medulla, and presents evidence linking lipomatosis to the transformation of the supporting cells of lymph nodes (fibroblasts) into adipocytes (fat cells). They also show that specific types of fibroblasts located in the medulla are more prone to become adipocytes.

The study shows that even at early stages of lipomatosis, negative changes arise that impair the ability of the lymph node to provide effective immunity. Among other observations, they note that the specialised blood and lymphatic vessels that normally provide channels for immune cells to enter and leave the lymph node are destroyed in the parts of the node where fat has formed. Lipomatosis of lymph nodes, even at early stages, may therefore be one important factor behind the poorer response to vaccinations observed in elderly people. Ultimately, the fat completely takes over the lymph node and it loses its ability to function.

Stromal transdifferentiation drives lipomatosis and induces extensive vascular remodeling in the aging human lymph node

Lymph node (LN) lipomatosis is a common but rarely discussed phenomenon associated with aging that involves a gradual exchange of the LN parenchyma into adipose tissue. The mechanisms behind these changes and the effects on the LN are unknown. We show that LN lipomatosis starts in the medullary regions of the human LN and link the initiation of lipomatosis to transdifferentiation of LN fibroblasts into adipocytes. The latter is associated with a downregulation of lymphotoxin beta expression. We also show that isolated medullary and CD34+ fibroblasts, in contrast to the reticular cells of the T-cell zone, display an inherently higher sensitivity for adipogenesis.

Progression of lipomatosis leads to a gradual loss of the medullary lymphatic network, but at later stages, collecting-like lymphatic vessels are found inside the adipose tissue. The stromal dysregulation includes a dramatic remodeling and dilation of the high endothelial venules associated with reduced density of naïve T-cells. Abnormal clustering of plasma cells is also observed. Thus, LN lipomatosis causes widespread stromal dysfunction with consequences for the immune contexture of the human LN. Our data warrant an increased awareness of LN lipomatosis as a factor contributing to decreased immune functions in the elderly and in disease.

What To Do About the Aging of the Glymphatic System?
https://www.fightaging.org/archives/2022/12/what-to-do-about-the-aging-of-the-glymphatic-system/

It is becoming increasingly clear that issues in the drainage of cerebrospinal fluid from the brain play an important role in the onset of neurodegenerative conditions in late life. Neurodegenerative conditions are associated with a build up of various forms of molecular waste, such as toxic misfolded and otherwise altered proteins, in and around brain cells. It is likely that other stress signaling that provokes chronic inflammation in brain tissue is effectively amplified in effect as the drainage channels that normally carry metabolic products from the brain are reduced in capacity with age.

Leucadia Therapeutics has focused on the drainage path for the olfactory bulb, through the cribriform plate, in the development of Alzheimer's disease, which begins in this area of the brain specifically. The rest of the research community, meanwhile, is largely interested in the glymphatic system (including meningeal lymphatic vessels) in the context of cerebrospinal fluid drainage. Like the broader lymphatic system, the glymphatic system that drains the brain suffers a range of issues with age that reduce its capacity. Unlike the cribriform plate, there really isn't an obvious starting point for the development of ways to restore this drainage capacity. It seems likely that this is needed, however, and if achieved would significantly slow the degenerative aging of the brain.

Overview of the meningeal lymphatic vessels in aging and central nervous system disorders

The central nervous system (CNS) has been considered a relatively immune-privileged site. While the neuroimmune interactions play an important role in diverse neurological disorders, immune surveillance of the CNS remains unclear. The CNS contains microglia, but these cells are confined to the brain parenchyma and cannot interact with peripheral immune system under healthy conditions. Unlike the brain parenchyma, the meningeal lymphatic network enables immune surveillance of the brain efficiently. The discovery of meningeal lymphatic vessels (MLVs) in the CNS has shattered the traditional notion that the CNS is immune-privileged. Aging is accompanied by a functional decline of MLVs, which contribute to several age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), brain tumors, traumatic brain injury (TBI), multiple sclerosis (MS), and stroke.

Over the past few years, evidence for MLVs in the CNS has been accumulating. Recent studies revealed that some features of the meningeal lymphatic system are also present in humans. Defects in MLVs, which excrete metabolic wastes from the CNS to peripheral surroundings, are implicated in various neurological disorders. Although the contribution of MLVs in these diseases is not completely understood, the accumulation of metabolites, cellular debris, and misfolded proteins in the brain due to impaired drainage, which cannot be transported to deep cervical lymph nodes (dCLNs), may play key roles. It has been gradually recognized that the CNS relies on the function of MLVs to maintain homeostasis, and the draining function of MLVs also decreases with age.

However, for many CNS diseases, the causal relationship between MLVs and neuropathological changes is not fully clear. Here, after a brief historical retrospection, we review recent discoveries about the hallmarks of MLVs and their roles in the aging and CNS diseases, as well as potential therapeutic targets for the treatment of neurologic diseases.

A Look Back at 2022: Progress Towards the Treatment of Aging as a Medical Condition
https://www.fightaging.org/archives/2022/12/a-look-back-at-2022-progress-towards-the-treatment-of-aging-as-a-medical-condition/

At the end of 2022, we can reflect on the fact that we are steadily entering a new era of medicine, one in which mechanisms of aging are targeted rather than ignored. It is a profound change, one that will change the shape of a human life and ultimately the human condition by eliminating the greatest sources of suffering and death in the world. Year after year, we see increased funding, ongoing progress towards therapies capable of slowing aging or reversing aspects of aging, and a growing taxonomy of such potential therapies and their target mechanisms.

The view of aging in the medical community and public at large is changing, slowly, in the face of this, such as the recognition that the long-established practice of dividing aging into many different diseases and treating them one by one isn't working. To fight aging one must tackle the causes of aging, and each cause contributes to multiple conditions. One day in the not-so-distant future, the average person in the street will see aging the same way that he or she presently sees cancer, meaning that it is obviously a research priority, something that should be treated and cured.

The Longevity Industry and Associated Non-Profit Initiatives

The longevity industry continues to grow and diversify, and there are now far too many companies and too many venture funds for any one observer, and certainly not this one, to keep up with new teams, new funding, and new projects. Much the same could be said for the non-profit space. The organizer and volunteers at AgingBiotech.info are certainly doing their best to maintain a useful, up-to-date resource, however!

That said, I will note a few items, starting with one sizable fund, Kizoo Technology Ventures, that was profiled earlier this year. It is an important fund because its principals specifically focus on the SENS view of aging: the importance of molecular damage, and the point that rejuvenation will only be achieved by repairing that damage. The SENS Research Foundation released its annual reports a few months ago, and it is, as always, interesting reading for those interested in the science of rejuvenation. Aubrey de Grey has launched a new non-profit, the Longevity Escape Velocity Foundation that will focus on similar work to that conducted at the SENS Research Foundation, with an emphasis on repairing the cell and tissue damage that causes aging.

Fundraising activity was quite energetic prior to the recent market downturn. While many of these companies are actually working on drug discovery platforms or next generation dietary supplements or other low-hanging fruit rather than bold new therapies, there are nonetheless exciting biotechnologies under development as well, true means of rejuvenation. We'd always want to see a larger portion of the industry undertaking that sort of work, but it is what it is. As growth occurs, it is interesting to see the rush to moderation in messaging. It is a longevity industry, yes, but one in which the larger players are quick to reassure the world that they are not in fact trying to produce longevity.

Cellular Senescence

Cellular senescence is an important contributing cause of aging, in that the burden of senescent cells rises with age, and these cells disrupt tissue and organ function with their pro-growth, pro-inflammatory signaling. Researchers are optimistic regarding the potential of therapies targeting senescent cells, even the cautious types, and so is the popular science press. In just the last year, many studies have reported slowing or reversal of specific aspects of aging via clearance of senescent cells, or otherwise implicated senescent cells in disease progression. A partial list: neurogenesis; neuronal function; Alzheimer's disease, liver disease; kidney aging; T helper cell function; atrial fibrillation; reducing pain but not cartilage damage in osteoathritis; loss of microvasculature; atherosclerosis; fibrosis and inflammation in NASH; diabetic macular edema; particularly senescence in vascular smooth muscle; pulmonary fibrosis, amyotrophic lateral sclerosis; chronic obstructive pulmonary disease, and age-related loss of pulmonary function via a range of mechanisms; failure of organ transplants; loss of regenerative capacity in the heart; cardiovascular disease in general; cognitive function and brain aging in late life; amyloid aggregation in the vasculature; sarcopenia via reduced stem cell function; osteoporosis was frequently discussed; disc degeneration; vascular calcification; Parkinson's disease, such as via removing senescent microglia; improving ischemic stroke recovery; accelerated aging due to induction of cellular senescence by chemotherapy and radiotherapy; abdominal aortic aneurysm; immune function in the brain; gum disease.

Clearing senescent cells should be synergistic with stem cell therapies and partial reprogramming, both combinations expected to provoke regeneration. Senolytics should also be synergistic with cancer therapies, providing better patient outcomes with fewer long-term side-effects. These combinations should receive more attention! Further, some research suggests that combinations of senolytics may synergize to improve on the results of any single drug.

New clinical trials continue to be launched for established senolytics, including one for Alzheimer's disease, and senolytics as a class are approaching clinical use. Novel approaches to reducing the burden of senescent cells continue to emerge as the wheels of drug development begin to turn in earnest. Those mentioned in the last year include the following: use of 25-hydroxycholesterol; improving the efficiency of natural killer cells via several approaches; mitochondrial transfer; applying partial reprogramming to senescent cells, something that continues to seem a bad idea; MCL-1 inhibition; control of viral infection; YAP upregulation; mitochondrially targeted tamoxifen; glutaminase inhibition; overexpression of GPNMB; inhibiting the BDNF-TrkB interaction; p53 upregulation; SFRP4 inhibition; overexpression of DDIT4 and HDAC4; PD-L1 checkpoint inhibition; GATA4 inhibition; USP16 inhibition; reducing mitochondrial dysfunction to prevent the onset of some cellular senescence; targeting antoxidants to telomeres; nintedanib, a similar drug to dasatinib; derivatives of FOXO4-DRI.

Mitochondrial Dysfunction

Mitochondrial dysfunction is a prominent feature of aging, and is accompanied by a decline in mitophagy, meaning the cell maintenance processes of autophagy targeted to mitochondria. Attempting to upregulate mitophagy is a popular topic, with approaches mentioned this year including urolithin A (and a clinical trial), BNIP3 upregulation, and iterations on spermadine. Unfortunately none of the easier, supplement based approaches appear to be any better than exercise or calorie restriction when it comes to improve the operation of autophagy in older individuals. There are other stress responses that can be triggered to improve mitochondrial function, such as the unfolded protein response, influenced via protein import mechanisms.

A range of other potential paths to reversing mitochondrial dysfunction are under development. Reprogramming is one of the more prominent, followed by the various groups developing the basis for mitochondrial transfer therapies. Researchers recently demonstrated editing of mitochondrial DNA in vivo, though it seems challenging to use this technology to deal with stochastic mutational damage. The role of mitochondrial DNA mutation remains much debated, both for and against. Other approaches mentioned this year include: enhancing mitochondrial fission to restore the imbalance in mitochondrial dynamics; magnetic fields used to improve mitochondrial function; use of antifibrosis drugs to improve mitochondrial metabolism; use of mitochondrially derived peptides; sirtuin upregulation; upregulating NAD levels via NMN supplementation and CD38 inhibition; partially inhibiting complex I of the electron transport chain; and mitocondrial uncoupling via newer, safer means than in past decades. Too few of these approaches seem likely to have large effect sizes, unfortunately.

Clocks for Aging

The number of clocks that assess biological age, derived from omics data and other measures, is proliferating rapidly. Even only considering epigenetic clocks the number is steadily increasing. Fortunately, at least some effort is being put into comparing clocks in order to winnow out the less helpful ones. New clocks noted this year incuded: a retinal image clock; a metabolomics clock; a clock for naked mole-rats; and a lipid clock.

This broadening of work on clocks is taking place because a consensus measure of aging would revolutionize the field, enabling rapid, directed progress towards the best approaches to treat aging as as medical condition. This point is widely recognized. We are not there yet, however, as the clocks developed to date are not yet well enough understood. Despite a few inroads, the connections between epigenetic aging and the rest of aging are not yet well mapped.

There appear to be some odd blind spots in many clocks, such as inflammatory status and biases in centenarian epigenetic age. Reduced epigenetic age does not prove slowed or reversed aging, we should probably be suspicious of clocks that use few data points, and all studies measuing clock data must also measure other metrics of health and disease. This state of affairs is not preventing speculation as to whether the existence of cross-species clocks should mean that therapies that actually address root causes of aging should perform equally well between species, or that epigenetic clocks will point the way to a true identification of the causes of aging.

Partial Reprogramming

There is so much money flowing into the exploration of partial reprogramming with Yamanaka factors and potential alternatives, in order to restore more youthful epigenetic patterns and thus more youthful cell behavior, that we're going to see a great deal of coverage, even in the popular press, in the years ahead. Hopefully the obstacles are overcome, such as the inclination of natural killer cells to attack reprogrammed cells, and the techniques improved, and this turns out to be a viable path to rejuvenation at the end of the day. It can't fix everything, but we can hope that it will positively influence many aspects of aging.

The fundamental research in animal models is getting funded as well, and continues apace. Progress in understanding and capabilities is quite rapid. If interested in the present state of play and the road to the clinic, there were a number of popular science overviews published following the large-scale funding of Altos Labs and other companies. Alternative approaches to reprogramming beyond Yamanaka factors are being considered. Is it possible to reprogram effectively with small molecules? Time will tell. Researchers are starting to think about the specific conditions they might treat with reprogramming approaches. Some of those metioned in the last year include: disc degeneration; T cell exhaustion resulting from cancer; and liver injury.

Neurodegeneration

Neurodegeneration is connected to near all of the mechanisms and environmental factors studied in the context of aging. Novel approaches to the treatment of neurodegenerative conditions are constantly suggested, and existing approaches mentioned while under development. A selection from the past year includes the following items: the use of disaggregases to clear amyloid, while noting that amyloid is still the primary focus in Alzheimer's treatment, despite continued failures in clinical trials; forcing microglia into the anti-inflammatory M2 polarization, or clearing them entirely; TREM2 antibodies to prevent the incapacity of microglia in the aging brain; transfer of cerebrospinal fluid from younger donors; a combination of rapamycin, acarbose, and phenylbutyrate; adjusting the aging gut microbiome; greater control of viral infection, particular those involving herpesviruses capable of persistent infection; whole blood exchange to encourage amyloid-β to leave the brain into the vasculature; reprogramming astrocytes into neurons in vivo; drugs to decrease microglial inflammation slow neurodegeneration in early stages; influenza vaccination correlates with a 40% reduced Alzheimer's risk; transcranial direct current stimulation; provoking greater activity in neural progenitor cell populations; Atoh1 gene therapy to regenerate hair cells in the inner ear; activating or somehow expanding the limited supply of precursor neurons; immunization against amyloid-β; use of plasmalogens; GM-CSF treatment improves memory in mice; enhancing neurogenesis to treat Alzheimer's, such as via upregulation of oxytocin.

The good news is that manifestations of neurodegenerative processes, such as cognitive impairment, are in decline, and those on the path to dementia can now be screened early, years in advance of symptoms. This lowered risk is likely the result of improved cardiovascular health, while individually reduced risk is offset by the aging and growth of the population, leading to higher absolute incidence of disease. Being fitter correlates with better late life cognitive function, and exercise with improved synaptic function, as well as improved brain function more generally. Physical fitness also clearly reduces dementia risk and improves brain function, perhaps largely via lowered blood pressure, with as much as 40% of dementia cases being the result of lifestyle choices.

Aging of the Immune System

Chronic unresolved inflammation is a key feature of aging. Immune system aging is these days described as a mix of immunosenescence and inflammaging; every year a few review articles discuss the definitions and relationship between them. Important areas of declining function include the thymus and hematopoietic populations in the bone marrow, though every aspect of the immune system shows loss of function. The thymus atrophies with age, a sizable contribution to the decline of the adaptive immune system. Modest calorie restriction in humans has been shown to produce a surprisingly large regrowth of active thymus tissue, a surprising result that suggests the thymus is more dynamic in adults than suspected. KGF overexpression and introduction of subpopulations of thymic cells produces an enlarged thymus in animal studies, but would need a clever delivery mechanism to get the therapy into the thymus in humans.

Various approaches are under consideration to reverse immune aging, either generally or focused only on narrow issues within the broader set of problems. Lowering the lifetime burden of infection will likely slow hematopoietic aging. Upregulation of autophagy might help slow immune aging. A gene therapy delivering a BPIFB4 variant improved immune function in old mice. PGD2 inhibition can help with the slowdown in some narrow aspects of immune cell communication, improving the immune response. Trained immunity is an interesting phenomonen in which some challenges can improve innate immune function in late life. For example, vaccination with mycobacterium vaccae suppresses chronic inflammation. Calorie restriction has similar effects on innate immune system activation. Lowering inflammation may be a useful treatment for frailty. Targeting the inflammasome may be an improvement on current very blunt methods of suppressing inflammatory signaling, and clearing senescent cells to remove their inflammatory signaling should also help greatly. Other approaches to lowering inflammation mentioned recently include resistance training in older adults and reduced SPARC levels in fat tissue.

The Gut Microbiome in Aging

The balance of populations in the gut microbiome changes with age in detrimental ways, such as via increasing inflammatory signaling, producing harmful metabolites, or a diminished production of beneficial metabolites. This impacts health, and numerous correlations can be drawn between the activity of the microbiome and various manifestations of aging. Adjusting the gut microbiome in lasting ways to restore youthful populations may or may not achieve that much more than choosing a good program of exercise and diet, but it can be accurately measured. One can determine exactly what happened following any given intervention via the sequencing of microbes from a stool sample. Various approaches move the needle, and those in the spotlight this past year include: calorie restriction and methionine restriction; fecal microbiota transplantation was shown to improve function in mice, and this approach was a particularly popular topic in the lead in to FDA approval of one implementation and a few results in aged humans; oral administration of Akkermansia muciniphila; and heterochronic parabiosis, the latter obviously more interesting than useful.

Cardiovascular Disease

Atherosclerosis and consequent cardiovascular disease is the largest single cause of human mortality, and should be a high priority in research and development. A great deal of evidence points to the inflammation of aging as a major driver of atherosclerosis. At the core of the condition, there is macrophage dysfunction where cholesterol overwhelms cells in artery walls. Calcification of vascular and heart tissue occurs in parallel with atherosclerosis, and is known to raise the risk of stroke as well as other cardiovascular events.

Numerous approaches have been suggested in the past year as treatments for cardiovascular diseases and their consequences: upregulation of autophagy; TRPM2 inhibition; targeting matrix vesicles to reduce pro-calcification signaling; CCL17 inhibition reduces inflammation in cardiac hypertrophy; an oligodendrocyte cell therapy, the cells responsible for generating myelin, improves stroke recovery, as does PTPσ inhibition; influenza vaccination can reduce inflammation to reduce stroke risk. Cholesterol continues to be the primary focus of therapeutic development in cardiovascular disease, such as via upregulation of reverse cholesterol transport. Atherosclerosis is in principle highly preventable, and early detection of atherosclerotic lesions might encourage greater success on this front.

Vascular stiffening is a major feature of aging. It is driven in part by degeneration of elastin, but has a broad range of contributing mechanisms. It contributes to many pathologies, even only considering the downstream effects of resulting hypertension, such as vascular restructuring and pressure damage to delicate tissues. Controlling hypertension greatly reduces risk of stroke. Targeting the inflammasome in vascular tissues or the use of SGLT2 inhibitors may reduce the aforementioned vascular dysfunction. Inhibition of piezo1 signaling may block the connection between hypertension and vascular hypertrophy.

Cancer

Cancer is the second largest cause of mortality in our species. It is a numbers game: damage and cell replication versus the odds of the wrong combination of mutations occurring in a cell, leading to unfettered replication. We might imagine that any narrow rejuvenation therapy that improves regeneration and increases cell activity in later life, such as improving mitochondrial function, for example, is going to increase cancer risk. Still, it is clear that a better lifestyle more than halves cancer risk, even just considering exercise.

We might argue that targeting theraputics to cancer cells is the true key to success in treating cancer. Prodrugs are one way to achieve that goal, ensuring that the drug is only active in cells with certain chemical characteristics. One of the reasons why immunotherapies are an improvement over the older approaches of chemotherapy and radiotherapy is that immune cells inherently provide the basis for a targeted approach. Early CAR-T therapies are looking good; long-term remission has occurred in a significant number of patients. Since then, many potential approaches to improve immunotherapies have emerged, such as via engineering T cells to reduce exhaustion in the face of exposure to cancer cells, replacement of checkpoint inhibition with new varieties of T cell therapies, or mRNA cancer vaccines.

Regenerative Medicine

Cell therapies and extracellular vesicle therapies of various sorts are under development for many conditions, including those in which cells are made universal to allow transplantation between individuals, though arguably we don't well understand the more widely used forms of stem cell therapy that presently exist. Some of the stem cell and vesicle therapies mentioned in the past year follow: cell therapies for degenerative disc disease and spinal cord injury; stem cell derived vesicles can reduce epigenetic age; cells sourced from the peripheral nervous system can be used to treat neurodegenerative conditions; brain regeneration might be achieved through suitable cell therapies; first generation stem cell and exosome therapies can upregulate neurogenesis; improving muscle regrowth with vesicles, and using exosomes to treat ventricular arrhythmia­.

Beyond cell therapies, growing and then implanting organoids may have utility, augumenting aged organs with new and functional tissue. Additionally, the use of scaffold material implants continues to be developed, such as for regrowth of dental pulp. Further, organ replacement may benefit from the advent of engineered pig organs; the first such heart transplant was performed this year, but the challenges encountered suggest that a longer road than hoped lies ahead before widespread use.

Is it possible to manipulate native cells to induce regeneration? Targeting fibroblasts to alter their behavior may enable scarless healing in mammals, for example, or reprogramming fibroblasts to cardiomyocytes in the heart. Engineering regrowth of organs in adults is potentially possible, given that highly regenerative species are capable of it, and non-regenerative species can perform much the same feats of regeneration during embryonic development. Enhancer sequences from zebrafish can be used to spur heart regeneration in mice. Further, researchers managed to imperfectly regrow frog limbs using a cocktail of growth factors; the result was not a fully formed limb, but that it worked at all suggests that this line of research may have potential.

Regulation of Medical Development

Early in the year, I noted a charitable view of the problems at the FDA regarding the development of drugs to treat aging. Meanwhile the wrangling continues over the question of whether largely unaccountable international bodies will decide to classify aging as a disease, something that is of importance to the regulation and funding of medicine and medical research, but irrelevant to the science itself. Longevity industry companies involved in developing therapies to treat aging are ignoring this circus in favor of picking specific diseases of aging and proceeding through the regulatory gauntlet as-is, in expectation that widespread off-label use will result. Still, comparatively few trials of genuinely age-targeted therapies have yet taken place. These are still early days.

Cryonics and Cryopreservation

That there should be more support for cryonics research and development is a popular viewpoint in that side of the longevity community. Until recently, cryonics was largely a non-profit industry. It has been proposed that a path to for-profit cryonics might involve first starting a hospital (or a veterinary clinic), and then adding cryonics services to that business, rather than starting with dedicated cryonics providers. Some new capabilities may pay off more than others when it comes to generating greater funding and growth for the cryonics industry, such as reversible vitrification of organs for use in transplantation. At some point in the future, a tipping point will be reached, and cryonics will have its time in the sun, just as the once-fringe field of rejuvenation research is enjoying that time in the sun today.

Rewarming tissue for use without damaging cells, structures, and function is arguably the real challenge in cryopreservation; in the last year use of magnetic nanoparticles has shown potential as a solution that might at least be applied to organs intended for transplantation.

Thoughts and Short Essays

I occasionally set down a few thoughts on topics relevant to longevity. Here are the few times that happened in the past year:

• Be Extraordinary or Be Dead
• Request for Startups in the Rejuvenation Biotechnology Space, 2022 Edition
• A Hypothetical Project: the Fast Track to Partial Reprogramming in Human Volunteers
• Should I Actually Be Working on Cryonics Rather than Rejuvenation?
• Understanding Anencephaly as the Start on the Road to Building Replacement, Youthful Bodies
• Is Reversing Paracrine Senescence a Useful Approach to Alleviating the Age-Related Burden of Senescent Cells?
• Distributed Full Disclosure Medical Development
• A Short Commentary on Why We Advocate for Aging
• Reporting on a Study of One with Khavinson Peptides and Melatonin for Thymic Regrowth
• Two Year Update on a Study of One with Flagellin Immunization to Adjust the Gut Microbiome
• Notes from the Rejuvenation Startup Summit, Held in Berlin in October 2022
• Year End Charitable Donations to Help Advance Rejuvenation Research

Onwards!

Things move slowly when you look at the world a year at at time. They run quite fast when comparing today with ten years ago, or ten years from now. There was no such thing as a longevity industry ten years ago, for example. Ten years from now, doctors will be widely prescribing the first rejuvenation therapies, and it will be the common wisdom that one can and should be treated to slow and reverse processes of aging. We live in interesting times, a great transition over decades from a world in which aging was thought of as immutable to a world in which aging is just another medical condition to be addressed.

Progress Towards Decoupling Epigenetic Rejuvenation from Cell Identity Change in Partial Reprogramming
https://www.fightaging.org/archives/2022/12/progress-towards-decoupling-epigenetic-rejuvenation-from-cell-identity-change-in-partial-reprogramming/

Reprogramming cells using the Yamanaka factors produces both a reset of epigenetic patterns to a more youthful configuration and a change in cell identify. One of the primary challenges inherent in reprogramming to achieve rejuvenation is avoidance of this altered cell identity. Reprogramming isn't an immediate switch, it is a slow process over hours to days, but a fraction of reprogrammed cells do change into induced pluripotent stem cells after some period of exposure to reprogramming factors. This is an undesirable outcome when delivering a reprogramming therapy; if new approaches can be found that do not alter cell identity, that would make reprogramming a much more viable basis for rejuvenation treatments.

Partial somatic cell reprogramming has been touted as a promising rejuvenation strategy. However, its association with mechanisms of aging and longevity at the molecular level remains unclear. We identified a robust transcriptomic signature of reprogramming in mouse and human cells that revealed co-regulation of genes associated with reprogramming and response to lifespan-extending interventions, including those related to DNA repair and inflammation. We found that age-related gene expression changes were reversed during reprogramming, as confirmed by transcriptomic aging clocks.

The longevity and rejuvenation effects induced by reprogramming in the transcriptome were mainly independent of pluripotency gain. Decoupling of these processes allowed predicting interventions mimicking reprogramming-induced rejuvenation (RIR) without affecting somatic cell identity, including an anti-inflammatory compound osthol, ATG5 overexpression, and C6ORF223 knockout. Overall, we revealed specific molecular mechanisms associated with RIR at the gene expression level and developed tools for discovering interventions that support the rejuvenation effect of reprogramming without posing the risk of neoplasia.

Monocytes Become More Inflammatory with Age
https://www.fightaging.org/archives/2022/12/monocytes-become-more-inflammatory-with-age/

Monocytes of the innate immune system react to changes in the aging tissue environment by becoming more inflammatory. Those changes include the signaling of growing numbers of senescent cells, the presence of DNA debris from stressed cells, and the like. The innate immune system makes the issue worse by ensuring a state of chronic inflammation that disrupts normal tissue maintenance and function. Finding ways to suppress the inflammation of aging, such as the targeted removal of senescent cells, is an important goal in the treatment of aging as a medical condition.

It has been widely accepted that monocytes are one of the central mediators contributing to inflammaging. However, it remains unclear whether aged monocytes, similar to aged T cells, have characteristics of hyperactivation and increased expression of co-inhibitory molecules. Here, peripheral blood mononuclear cells (PBMCs) were isolated from young (21-40 years old), middle-aged (41-60 years old), and older human subjects (older than 60 years old). Flow cytometry was used to monitor changes in the expression of surface molecules of monocyte subsets and cytokine-producing capacity.

We observed increased TNF-α and decreased IL-6 production in monocytes from older adults compared with young and middle-aged adults. Older adults had a greater percentage of intermediate and non-classical monocyte subsets, along with increased levels of the immune activation markers HLA-DR, and adhesion molecules CD11b and CD62L. Furthermore, we observed increased CCR2 expression on classical monocytes and decreased CX3CR1 expression on non-classical monocytes in older adult subjects. The expression of co-inhibitory receptors was reduced on monocyte subsets in older adults.

In conclusion, circulating monocytes in older adults exhibit increased expression of activation, adhesion, and migration markers, but decreased expression of co-inhibitory molecules.

MERTK Inhibition Increases Bone Density via Increased Osteoblast Activity
https://www.fightaging.org/archives/2022/12/mertk-inhibition-increases-bone-density-via-increased-osteoblast-activity/

Bone density results from the balance of constant activity on the part of osteoblasts and osteoclasts, the former building bone, the latter breaking it down. With advancing age, the balance of activity shifts to favor osteoclasts, producing a gradual loss of bone density that leads to osteoporosis. Therapies have to date typically attempted to reduce osteoclast activity, but researchers here note an approach based on increased osteoblast activity.

Bones appear to be durable and solid. But appearances are deceptive: in fact, bone tissue is in a constant state of remodeling. Bone-degrading osteoclasts and bone-building osteoblasts ensure a fine balance in the healthy organism. But this balance is occasionally disturbed: in osteoporosis, bone resorption takes over, so that fractures and deformities can occur. Bone metastases, which occur in the course of many cancers, are also often caused by bone resorption processes. This is also true for multiple myeloma, which originates and spreads in the bone marrow.

So far, drugs are available that inhibit bone resorption by osteoclasts. However, researchers believe that agents that promote bone formation by osteoblasts are also medically necessary. To identify such substances, the researchers first had to find out which signaling pathways control osteoblast activity. The team identified in mouse osteoblasts the two enzymes MERTK and TYRO3, so-called receptor tyrosine kinases, which regulate bone production. The function of the two enzymes was studied in mice in whose osteoblasts either one or the other receptor tyrosine kinase was genetically switched off. The result: If MERTK was inactivated, the bone mass of the animals increased. Without TYRO3, on the other hand, it decreased.

The small-molecule agent R992 inhibits MERTK activity. When healthy mice were treated with R992, their osteoblast numbers increased and the animals' bone mass increased. Treatment with R992 also reduced bone loss and the number of bone metastases in mouse models with myeloma, lung cancer, and breast cancer cell lines. The agent R992 is not approved as a drug. To potentially study the effects of MERTK blockade in patients, the team is currently developing an antibody that specifically blocks the function of MERTK.

eIF2α as a Target to Prevent T Cell Stress and Loss of Function in Cancer Immunotherapy
https://www.fightaging.org/archives/2022/12/eif2%ce%b1-as-a-target-to-prevent-t-cell-stress-and-loss-of-function-in-cancer-immunotherapy/

Researchers here identify eIF2α as a target for interventions that prevent T cells from shutting down after prolonged activity in a tumor environment. The stress response to extended activity is normally protective, but in this case it prevents T cells from being as effective as they might be, which contributes to an established tumor's compromise of the immune system. This sort of approach offers the promise of improving cancer immunotherapies, increasing the damage that each T cell can do to tumor tissue.

The stress response in T cells can lead to their inability to curtail tumor growth. Researchers found that T cells exposed to the environment of solid cancers undergo a natural response to stress that shuts off their function, limiting T cell ability to kill tumors. By manipulating multiple proteins in the stress response pathway inside T cells, the team showed that it was possible to overcome the intrinsic T cell stress response to allow the immune system to thwart cancer growth.

At the center of this research is a protein called PKR ER-like kinase (PERK), which is a major stress sensor for all cell types, including T cells, but has not been deeply studied in the context of immunity. That is, when a T cell is under duress - like when faced with the hostile environment created by cancer cells - it is PERK that responds to the stress in a way that causes cells to stop secreting proteins in an effort to help the cell survive.

Researchers found that when PERK is activated, modification of one molecule called phosphorylated eIF2-alpha is responsible for the T cell momentarily stopping protein synthesis during the stress response. When researchers forced phosphorylated eIF2-alpha to cease its natural function, the T cells continued protein synthesis, and T cells were able to continue to control tumor growth in mice. This research shows that it is very possible to tweak T cells genetically or pharmacologically to enhance their ability to battle cancer tumor cells.

Notes on the 2022 Longevity Summit at the Buck Institute
https://www.fightaging.org/archives/2022/12/notes-on-the-2022-longevity-summit-at-the-buck-institute/

The Buck Institute recently hosted the 2022 Longevity Summit, and here find some notes on the event from a participant. The number of conferences dedicated to the field of longevity science is increasing steadily, year after year. The best are those in which one finds a mix of entrepreneurs, scientists, and investors, all networking to advance the state of the art in the treatment of aging as a medical condition.

The Longevity Summit at the Buck Institute, a relatively short two-day geroscience and longevity biotech conference held on December 6-7, was nevertheless densely packed with new research - to the point where we can only cover some of the talks here. The conference was organized by Longevity SF, a nonprofit organization founded by the CEO of NeuroAge Therapeutics.

The event opened with a lecture by Buck director Dr. Eric Verdin, who presented some fascinating new research fresh out of the institute's labs. Dr. Verdin's talk touched on one of the most important topics in today's geroscience: finding reliable biomarkers of aging. The next speaker was Morgan Levine, who is one of the best experts on epigenetic clocks and currently with Altos Labs. Levine described her team's work on bringing existing epigenetic clocks closer to her definition of the perfect biomarker of aging.

Dr. Priyanka Joshi, co-founder of NeuroAge, started her presentation by asking the audience whether they believed the amyloid theory of aging. Just like in the longevity community in general, there seemed to be no consensus in the crowd. Whether or not the theory is correct, it is clear that aggregated proteins fail to perform their functions. Neuroage is working on a large postmortem cohort of about 2000 brains, analyzing them using various biological age clocks. The main takeaway is that people whose biological age was younger than their chronological age at death, were less likely to have developed Alzheimer's. Based on this and other insights, NeuroAge has developed a proprietary platform to identify protein products that are specific to slowing brain aging and eventually develop therapeutics against Alzheimer's and other protein misfolding diseases.

Sergio Ruiz, CEO of Turn.bio, presented the company's latest work on CAR T cell rejuvenation. While Turn's solution based on cellular reprogramming can potentially be used in a wide variety of treatments, the company is currently focusing on the two low-hanging fruits that allow immediate commercialization: immunology and dermatology. CAR T cells are genetically modified cells usually procured from the patient themselves, which means there is already some cellular exhaustion due to age. Turn's technology can rejuvenate those cells to make them more aggressive in fighting cancer.

Angiotensin II Increases Oxidative Stress in Aging
https://www.fightaging.org/archives/2022/12/angiotensin-ii-increases-oxidative-stress-in-aging/

Researchers here suggest that angiotensin II expression is maladaptive in the context of aging, provoking greater oxidative stress and harmful downstream consequences for cell and tissue function. If looking to produce therapies based on interfering in angiotensin II receptor signaling, an approach already well established in the treatment of hypertension, the question is always the tradeoff between loss of function and avoidance of damage. Few if any molecular interactions in the body are entirely dispensable, and angiotensin II signaling is involved in a range of normal cellular processes. That said, this topic is well explored via the existing uses of angiotensin II receptor blockers.

For the last few decades, the involvement of the renin-angiotensin system (RAS) in mediating vasoconstriction, ion entry and excretion, fibrosis, inflammatory and oxidative stress has been well documented. In addition to the circulating system, elements of the RAS are also found in diverse tissues of the brain, heart, and kidney, and contribute to the aging of these organs. Within the brain, different components of the RAS have been extensively studied in the context of neuroprotection and cognition. Alterations in the brain RAS during aging may establish a link between impairment of autonomic reflex function and metabolic changes in aging. Further evidence for the relevance of the RAS in aging is derived from numerous experiments in vivo and in vitro, indicating that aging is accompanied by the increased activity of angiotensin II (Ang II), which is the major bioactive peptide of this system.

A prospective observational study effectively proved that the lifespan of mice with disrupted Ang II type 1 receptor (AT1R) was remarkably longer than that in the control group and showed that the mice lacking AT1R exhibited less oxidative damage, consequently indicating that Ang II-induced reactive oxygen species (ROS) by AT1R seemed to play a crucial part in the aging process. Considering that mitochondria are a key source of endogenous ROS and telomeres are particularly vulnerable to oxidative stress, in this article, we first describe the diverse components of the RAS as well as their physiological functions coupling with each other. Then, we provide an overview of the primary ROS sources and the mechanistic association of ROS with mitochondria and telomeres. This is followed by the discussion of the seemingly universal roles of mitochondrial dysfunction and telomere attrition in aging and how Ang II influences them, conducing to present new preventive strategies in fighting aging and age-associated diseases.

A Popular Science View of the Development of Senolytic Therapies
https://www.fightaging.org/archives/2022/12/a-popular-science-view-of-the-development-of-senolytic-therapies/

Over the last decade, an increasing diversity of research groups and companies are working towards the clinical use of senolytic therapies to reverse aspects of aging in older patients by clearing harmful senescent cells. Of the early senolytic therapies, the dasatinib and quercetin combination is the only one with published data in human clinical trials showing clearance of senescent cells. This treatment is in fact easily accessible to self-experimenters, and even being prescribed off-label by more adventurous physicians. The biotech industry is working to produce a next generation of (probably) better approaches, and obtain regulatory approval for their use. A decade from now, clearance of senescent cells in older people will be widespread, and the incidence of serious age-related disease will decrease by some noticeable amount as a result.

There is a growing research movement to halt chronic disease by protecting brains and bodies from the biological fallout of aging. If these researchers are successful, they'll have no shortage of customers: People are living longer, and the number of Americans age 65 and older is expected to double, to 80 million, by 2040. One of their targets is decrepit cells that build up in tissues as people age. These "senescent" cells have reached a point - due to damage, stress or just time - when they stop dividing, but don't die. While senescent cells typically make up only a small fraction of the overall cell population, they don't just sit there quietly. Senescent cells can release a slew of compounds that create a toxic, inflamed environment that primes tissues for chronic illness. Senescent cells have been linked to diabetes, stroke, osteoporosis, and several other conditions of aging.

These noxious cells, along with the idea that getting rid of them could mitigate chronic illnesses and the discomforts of aging, are getting serious attention. The National Institutes of Health is investing 125 million in a new research effort, called SenNet, that aims to identify and map senescent cells in the human body as well as in mice over the natural lifespan. And the National Institute on Aging has put up more than 3 million over four years for the Translational Geroscience Network that is running preliminary clinical trials of potential antiaging treatments. Drugs that kill senescent cells - called senolytics - are among the top candidates. Small-scale trials of these are already underway in people with conditions including Alzheimer's, osteoarthritis, and kidney disease.

Numerous medical companies have jumped on the anti-senescence bandwagon. But results have been mixed. One front-runner, Unity Biotechnology dropped a top program in 2020 after its senolytic medication failed to reduce pain in patients with knee osteoarthritis. More recently, however, the company reported progress in slowing diabetic macular edema, a form of swelling in the back of the eye due to high blood sugar. Despite the excitement, senolytic research remains in preliminary stages. A lot of basic and clinical research must happen first, but if everything goes right, senolytics might someday be part of a personalized medicine plan: The right drugs, at the right time, could help keep aging bodies healthy and nimble.

The SenNet Consortium Intends to Map Senescent Cells Throughout the Human Lifespan
https://www.fightaging.org/archives/2022/12/the-sennet-consortium-intends-to-map-senescent-cells-throughout-the-human-lifespan/

As noted last year, the NIH is setting up the SenNet program to fill in some of the larger gaps in the present detail-level knowledge of the role of senescent cells in aging. The goal is to better steer the numerous efforts presently underway to develop improved senolytic therapies that clear senescent cells from old tissues, thereby producing rapid rejuvenation. Senolytic therapies have produced promising results in animal studies, and the potential for this class of treatment to significantly improve late life health in humans is an attractive prospect.

Multiple lines of evidence suggest that senescent cells (SnCs) drive aging and diverse age-related diseases in preclinical models. Interventions targeting SnCs impact multiple morbidities of old age. In 2011, it was established that genetic clearance of SnCs delays the onset of multiple age-related pathologies in transgenic mice. In 2016, it was established that genetic clearance of SnCs in mice delays all-cause mortality, extending median not maximum lifespan, implicating SnCs in many diseases that kill mice, including cancer, chronic kidney disease, and cardiomyopathy. These genetic studies incentivized the development of senotherapeutics - drugs that selectively target SnCs, either killing them (senolytics) or suppressing the SASP (senomorphics). The first senolytics were described in 2015. Since then, dozens of senotherapeutics have been described, including natural products, repurposed drugs, proteolysis-targeted chimeras, and chimeric antigen receptor T cells.

Despite this promise of SnCs as a therapeutic target, there is sparse information about the identity and features of SnCs in human tissues. Little is known about where and when SnCs arise in humans or the extent of SnC and SASP heterogeneity in vivo. Such knowledge could guide therapeutic and organ-specific targeting of SnCs. Clearly, there is a compelling need to develop tools to map and identify human SnCs with spatial and temporal resolution. To address this need, the SenNet Consortium was created in 2021. The goal of SenNet is to functionally characterize the heterogeneity of SnCs in 18 tissues from healthy humans across lifespan at the single-cell resolution, using mice and other models and perturbations for validation.

A Circular RNA Regulates SYP Expression to Improve Memory Function in Mice
https://www.fightaging.org/archives/2022/12/a-circular-rna-regulates-syp-expression-to-improve-memory-function-in-mice/

Researchers here note that SYP expression declines with age and is involved in mammalian memory function. They find a circular RNA that uprgulates SYP expression, and use it to improve memory in a mouse model. Unfortunately the study didn't use normally aged mice, but rather an artificial model of chemically induced damage as accelerated aging. Nonetheless, there is sufficient existing evidence for the role of SYP to think that the results of this study support running a test in normally aged mice to see if a similar positive outcome can be achieved there.

Age is an established risk factor for neurodegenerative disorders. Aging-related cognitive decline is a common cause of memory impairment in aging individuals, in which hippocampal synaptic plasticity and hippocampus-dependent memory formation are damaged. Circular RNAs (circRNAs) have been reported in many cognitive disorders, but their role in aging-related memory impairment is unclear. In this study, we aimed to investigate the effects of circ-Vps41 on aging-related hippocampus-dependent memory impairment and explore the potential mechanisms. Here, D-galactose was used to produce a conventional aging model resulting in memory dysfunction.

Circ-Vps41 was significantly downregulated in D-galactose-induced aging in vitro and in vivo. The overexpression of circ-Vps41 could upregulate synaptophysin (Syp), thereby promoting the synaptic plasticity and alleviating cognitive impairment in aging mice. Mechanistically, we found that circ-Vps41 upregulated Syp expression by physically binding to miR-24-3p. Moreover, the miR-24-3p mimics reversed the circ-Vps41 overexpression-induced increase in Syp expression.

In conclusion, overexpression of circ-Vps41 alleviated the synaptic plasticity and memory dysfunction via the miR-24-3p/Syp axis. These findings revealed circ-Vps41 regulatory network and provided new insights into its potential mechanisms for improving aging-related learning and memory impairment.

Senescent Cells Inhibit Muscle Stem Cell Function and Regenerative Capacity
https://www.fightaging.org/archives/2022/12/senescent-cells-inhibit-muscle-stem-cell-function-and-regenerative-capacity/

Researchers here report on evidence for senescent cells in the stem cell niches supporting muscle tissue to reduce stem cell function and the capacity for muscle regeneration. Senescent cells accumulate with age throughout the body, and their inflammatory secretions are disruptive to tissue function. The development of many varied approaches to selectively destroy these errant cells is well underway in the biotech community, with the hope that late life health will be greatly improved as a result.

Tissue regeneration requires coordination between resident stem cells and local niche cells. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin, and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time, and ageing.

Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.