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  • Towards Control of Inflammation as an Important Goal in the Treatment of Aging
  • ASC Specks as a Sizable Contribution to Chronic Inflammation
  • Supporting Evidence for Somatic Mutations to be an Important Contributing Cause of Aging
  • A Non-Amyloid Biomarker for Early Alzheimer’s Disease
  • Calorie Restriction Slows Immune Aging in Part via Gut Microbiome Alterations
  • The SToMP-AD Trial of Senolytics Dasatinib and Quercetin for Alzheimer’s Disease
  • An Outline of Present Work on Partial Reprogramming as a Rejuvenation Therapy
  • Towards Partial Reprogramming to Treat Disc Degeneration
  • Calorie Restriction and mTOR Inhibition are Additive in Slowing Muscle Loss with Age
  • High Status Actors Live Longer than their Lower Status Peers
  • The Merits of Late Life Suppression of Growth Hormone Signaling
  • Age-Related Hearing Loss is Accompanied by Chronic Inflammation in the Inner Ear
  • Targeting IL-9 to Reduce Perivascular Fibrosis Resulting from Hypertension
  • Mcl-1 Inhibitors as a Novel Class of Senolytic
  • The 2022 Longevity Summer Camp for People Who Want to Work in the Longevity Industry

Towards Control of Inflammation as an Important Goal in the Treatment of Aging

Today I’ll point out a review article that laments the present state of progress towards the control of inflammation in the human body. While acknowledging that great strides have been made in ways to interfere in inflammatory signaling, benefiting many patients, present tools are crude in comparison to the technologies that will most likely be needed in order to truly control unresolved, chronic inflammation and eliminate its contribution to age-related disease. True control of inflammation would imply the ability to (a) trigger resolution mechanisms with specificity, avoiding impairment of the operation of inflammation where it is needed, or at least (b) remove the lion’s share of the causes of chronic inflammation. Both seem tall orders, but one or both must be achieved.

The reasons why old tissues generate inflammation are manifold. One of the better understood mechanisms is the presence of growing numbers of senescent cells, actively secreting pro-inflammatory cytokines. Further, the microenvironment of aged tissue contains damage-associated molecular patterns of various sorts, produced by stressed or dying cells, and which are a trigger for innate immune system overactivation. Visceral fat tissue is particularly at fault when it comes to ways in which cells can provoke the immune system via signals that are close enough to those produced during infection to rouse an inflammatory response. There are many distinct paths to inflammation, which makes controlling even a majority of them a daunting process. Hence the hope for some smaller set of points of intervention, perhaps to be found in the master regulators of inflammatory behavior that react to these diverse signals.

Nonresolving inflammation redux

A review in 2010 entitled “Nonresolving Inflammation” began, “Perhaps no single phenomenon contributes more to the medical burden in industrialized societies than nonresolving inflammation.” That view has not changed. In 2021, a leading thinker in the field wrote that “inflammation is associated with almost every major human disease”. That same year, 13,905 review articles flagged “inflammation” as a key word and 1,284 of them included “inflammation” in their titles. This not only reflects that the topic is important but underscores that we are struggling to get a grip on it.

Since 2010, the toll of inflammation on human health has not subsided, despite major advances in understanding of the underlying biology, the tireless efforts of drug developers, and the clinical success of several interventions, such as biologics that block signaling by interleukin-1β (IL-1β) or tumor necrosis factor-α (TNF-α) have driven the death toll from nonresolving inflammation to the highest level in the lifetime of anyone reading these words. Meanwhile, the striking but partial success of immuno-oncology has focused attention on the ability of intra-tumoral inflammation to either frustrate or assist the immunological control of cancer. Accordingly, efforts to resolve inflammation as a treatment for autoinflammatory and autoimmune diseases have been joined by efforts to modulate inflammation in the treatment of malignancies.

Despite an extensive preclinical and clinical anti-inflammatory pharmacopoeia, as yet there is no drug that abolishes nonresolving inflammation in the majority of people treated, in the sense that patients remain free of inflammation when they stop taking the drug. There is no single drug that benefits a substantial proportion of those treated for nonresolving inflammation no matter which inflammatory disease they have. Few drugs that afford substantial benefit by strongly mitigating nonresolving inflammation are free of the risk of major toxicities. There is no way short of clinical trials to establish which of the diseases that nonresolving inflammation underpins will be most responsive to a given anti-inflammatory agent. We do not have a non-empirical basis for rationally designing combination anti-inflammatory therapies.

Despite these challenges, there is reason for optimism. Earlier clinical advances have been stunning, among them the impact of antagonists of IL-1β and TNF-α on autoinflammatory diseases, rheumatoid arthritis, and inflammatory bowel disease. The marked increase in basic research into inflammation gives hope for a knowledge roadmap that will identify practically actionable, highly effective, and safely addressable pathogenic pathways for patients suffering from atherosclerosis, obesity-related metabolic syndrome, asthma, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, scleroderma, non-alcoholic steatohepatitis, Alzheimer’s disease, multiple sclerosis, and other diseases in which nonresolving inflammation plays a major role.

ASC Specks as a Sizable Contribution to Chronic Inflammation

Chronic inflammation is a serious issue in later life, contributing to the onset and progression of all of the common fatal age-related conditions. This unresolved inflammation arises for many reasons, such as the pro-inflammatory signaling produced by senescent cells, the reaction of immune cells to persistent pathogens, rising levels of molecular damage and stressed cells as a result of the aging tissue environment, and so forth. The challenge lies in identifying which of these mechanisms are the most influential. The only practical way to determine the relative importance of any specific contribution to chronic inflammation is to block just that mechanism, in isolation, and then see what happens.

This approach to discovery is illustrated in today’s research materials. ASC specks are involved inside cells in the formation of inflammasome protein complexes that drive some of the mechanisms of the immune response. These ASC specks can also escape cells in significant numbers, however, and thereafter act as an inflammatory signal themselves, independently of the inflammasome. How important is this contribution to the inflamed tissue environment? In this paper, researchers report on the effects of clearing ASC specks from tissue, via a novel approach, and thereby quantifying the degree to which they cause inflammation.

New approach against chronic inflammation

The cells in our body have a sophisticated alarm system, the inflammasome. Its central component is the so-called ASC protein. In the event of danger, such as an attack by a pathogen, many of these molecules join together to form a large complex, the ASC speck. This ensures two things: First, its activity causes the cell to accumulate large quantities of messenger substances, which can be used to summon the help of the immune system. And secondly, numerous pores are formed in the cell membrane through which these alarm molecules can reach the outside and fulfill their task.

These holes ultimately lead to the demise of the cell. At some point, the cell basically explodes and empties its entire contents into the tissue. The messenger substances that are now abruptly released then act like a last great cry for help. This triggers the immune system to mount a strong inflammatory response that contains the infection. That is why this mechanism of innate immune defense is hugely important. However, in this process, ASC specks also accumulate in the tissue and may persist there for a long time. “We have now been able to show in mice that their activity activates the immune system even after the threat has been averted. This can result in chronic inflammation, which severely damages the tissue.”

Researchers have now succeeded in preventing this undesirable effect. They used so-called nanobodies for this purpose. These agents are antibody fragments with a very simple structure. Researchers generated nanobodies that specifically target ASC and can dissolve the specks. “The mice in our experiments have rheumatoid and gout-like symptoms. After administration of the nanobody, the inflammation and also the general health of the rodents improved significantly.”

Nanobodies dismantle post-pyroptotic ASC specks and counteract inflammation in vivo

Our previous attempt to target ASC specks using conventional antibodies (Abs) resulted in increased inflammation in a silica-induced model of peritonitis. Anti-ASC Abs promoted the uptake of extracellular ASC specks by phagocytes leading to increased IL-1β release from macrophages and immune cell infiltration into the peritoneal cavity. This common feature of conventional Abs used for therapy encouraged the development of alternative approaches, including single-domain antibody fragments, such as nanobodies (VHHs), which are derived from larger heavy chain-only Abs found in camelids. We recently generated a VHH against human ASC (VHHASC), which we over-expressed in the cytosol of cells to study the molecular mechanisms involved in ASC oligomerization. We showed that VHHASC binds the caspase-recruitment domain (ASCCARD) of ASC, preventing formation of CARD/CARD interactions necessary to form full ASC specks.

In this study, we tested the therapeutic potential of VHHASC and a newly generated VHH against murine ASC (VHHmASC) to target ASC specks in vitro and in vivo. We show that pre-incubation of extracellular ASC specks with VHHASC abrogated their inflammatory functions in vitro. Recombinant VHHASC rapidly disassembled pre-formed ASC specks and thus inhibited their ability to seed the nucleation of soluble ASC. Notably, VHHASC required prior cytosolic access to prevent inflammasome activation within cells, but it was effective against extracellular ASC specks released following caspase-1-dependent loss of membrane integrity, and pyroptosis. Finally, systemic treatment with VHHmASC efficiently dampened the inflammation in mouse models of acute gout or chronic rheumatoid arthritis (RA).

Supporting Evidence for Somatic Mutations to be an Important Contributing Cause of Aging

In today’s open access paper, researchers presented data on the pace at which random mutational damage accumulates in the nuclear DNA of somatic cells over a lifetime, covering a range of mammalian species with differing body sizes and life spans. They looked only at the lining of the gut, a tissue in which cells replicate rapidly, and thus one might expect to find more mutations and thus data that is more easily analyzed. The researchers found that the burden of mutations in late life is remarkably consistent, the rate of mutation inversely correlated with species life span. This is suggestive that somatic mutations are either an important contributing cause of aging, or a side-effect that is strongly connected to an important contributing cause of aging.

How could random mutational damage in cells throughout the body contribute to aging? Most of that damage is irrelevant, as it occurs in genes that are not active, or in cells that will reach the Hayflick limit and be removed from tissue in a matter of days to months. Present thought is focused on the effects of mutations in stem cells and progenitor cells, as these mutations can spread widely in tissue to produce what is known as somatic mosaicism. A growing body of evidence links specific forms of somatic mosaicism with conditions ranging from cardiovascular disease to specific cancers.

Another item for consideration is the comparatively recent discovery that DNA double strand break repair may produce characteristic age-related epigenetic changes regardless of where in the genome it occurs. Mutation rates determined by sequencing the genome, as in the study here, reflect the combination of rate of damage and rate of successful repair. If the important difference between species is the incidence of damage, and particularly incidence of double strand breaks, then the ability of DNA damage to drive age-related epigenetic change may be the important factor.

We can speculate, but at the end of the day the only way to robustly determine whether or not a given mechanism is important in aging is to fix it and see what happens. In the case of stochastic nuclear DNA damage that is something of a tall order. Reversing arbitrary changes in nuclear DNA, cell by cell throughout the body, will remain beyond the capabilities of medical science for some time to come. We can instead envisage relatively near-term approaches, still years distant, such as the complete replacement of a stem cell population supporting a tissue subject to somatic mosaicism, or ways to prevent DNA double strand break repair from causing epigenetic change, and perhaps these would produce compelling data.

Somatic mutation rates scale with lifespan across mammals

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species.

Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3.

The inverse scaling of somatic mutation rates and lifespan is consistent with somatic mutations contributing to ageing and with somatic mutation rates being evolutionarily constrained. This interpretation is also supported by studies reporting more efficient DNA repair in longer-lived species. Somatic mutations could contribute to ageing in different ways. Traditionally, they have been proposed to contribute to ageing through deleterious effects on cellular fitness, but recent findings question this assumption. Instead, the discovery of widespread clonal expansions in ageing human tissues raises the possibility that some somatic mutations contribute to ageing by driving clonal expansions of functionally altered cells at a cost to the organism. Examples include the possible links between clonal haematopoiesis and cardiovascular disease.

Alternative non-causal explanations for the observed anticorrelation between somatic mutation rates and lifespan need to be considered. One alternative explanation is that cell division rates could scale with lifespan and explain the observed somatic mutation rates. Available estimates of cell division rates, although imperfect and limited to a few species, do not readily support this argument. More importantly, studies in humans have shown that cell division rates are not a major determinant of somatic mutation rates across human tissues.

Another alternative explanation for the observed anticorrelation might be that selection acts to reduce germline mutation rates in species with longer reproductive spans, which in turn causes an anticorrelation of somatic mutation rates and lifespan. Although selective pressure on germline mutation rates could influence somatic mutation rates, it is unlikely that germline mutation rates tightly determine somatic mutation rates: somatic mutation rates in humans are 10-20 times higher than germline mutation rates, show variability across cell types and are influenced by additional mutational processes. Overall, the strong scaling of somatic mutation rates with lifespan across mammals suggests that somatic mutation rates themselves have been evolutionarily constrained, possibly through selection on multiple DNA repair pathways. Alternative explanations need to be able to explain the strength of the scaling despite these differences.

A Non-Amyloid Biomarker for Early Alzheimer’s Disease

Alzheimer’s disease is the present poster child for neurodegeneration in late life, the condition that receives the most funding and the greatest attention. It exemplifies the complexity of neurodegeneration, exhibiting multiple interacting forms of pathology, with considerable room for debate over causes and relationships and the relative importance of contributing or associated mechanisms. Is it a condition caused by amyloid-β accumulation, where amyloid later becomes irrelevant as tau pathology takes over? Or is amyloid-β a side-effect of causes of chronic inflammation, where inflammation is the true cause of tau pathology? Or is Alzheimer’s something yet more complex, a feedback loop between differing causes, with the relative importance of any given contributing mechanism varying from patient to patient?

In parallel to the search for effective therapies to treat Alzheimer’s disease, researchers are also engaged in a search for better, more practical, more cost-effective ways to determine whether or not a patient is in the early stages of the condition. Much of this effort is focused on finding better ways to measure levels of amyloid-β in the brain. Given the present doubts about the role of amyloid-β, it may be that other biomarkers are a better choice, if they can be found. Today’s research materials are an example of this sort of investigation, focused on what can be found in blood samples, one of the easier approaches to testing. Another different but analogous line of research is focused on retinal scans, similarly an easier approach to obtaining information on the state of the central nervous system.

New Alzheimer’s biomarker may facilitate rapid diagnosis

Discovery of a unique ratio of metabolites from blood samples of early-stage Alzheimer’s patients promises to speed diagnosis, allowing earlier treatments to be initiated. “We were delighted to discover that the ratio of two molecules, 2-aminoethyl dihydrogen phosphate and taurine, allows us to reliably discriminate samples of early-stage Alzheimer’s patients from controls.”

Current attempts to diagnose Alzheimer’s disease from blood samples depend on the presence of amyloid fragments, the molecules that cause brain tangles and plaques. “We consider amyloid plaques to be a consequence rather than the cause of Alzheimer’s disease. What is exciting about this new discovery is that it does not depend on amyloid and the assay can be performed on analytical equipment that is already present in most large hospitals.”

A possible blood plasma biomarker for early-stage Alzheimer’s disease

Onset of Alzheimer’s disease (AD) symptoms is correlated with accumulations of misfolded proteins and protein fragments, particularly amyloidβ42 (Aβ42) plaques and a dense tauopathy of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau deposits in specific brain regions. There is a latency period between the initiation of AD-type neuropathology in the brain and onset of clinical symptoms. Discovery of new ways of diagnosing AD in the earliest stages, particularly those present during the latency period, could lead to new types of treatment, including reconsideration of previously failed drugs.

Various biomarkers associated with later stages of AD have been suggested including cerebrospinal fluid (CSF) and plasma biomarkers indicative of amyloid deposition, neuronal damage and loss, and the formation of NFTs, notably phosphorylated-tau (P-tau), Aβ42, total-tau (T-tau), as well as neurofilament light protein (NFL), while plasma concentrations of Aβ40 and Aβ42 may not be as useful in diagnosing AD. Biomarkers based on imaging assessing amyloid-beta plaques (PiB-PET scans), tau deposits (tau-PET), brain atrophy (structural MRI), memory-related activity patterns (fMRI), and decreased glucose metabolism (FDG-PET) have also been proposed. Nucleic acid biomarkers for AD have also been proposed.

We have sponsored an FDA-approved Phase IIa clinical trial of L-serine (NCT03062449) for early-stage Alzheimer’s disease patients. At the time they receive their initial diagnosis, based on the Clinical Dementia Rating (CDR) score, patients are offered entry into the clinical trial. We hypothesized that a unique metabolic biomarker of early Alzheimer’s disease could be identified by examining the physiological amino acids and the nitrogen containing compounds that are within these blood samples for the early disease state. Using an automated Amino Acid Analyzer along with confirmation from tandem mass-spectroscopy, we examined metabolites displaying clear differences between AD and control blood plasma samples. We found that the concentration of 2-aminoethyl dihydrogen phosphate normalized by taurine concentrations in blood plasma samples reliably identifies early-stage AD patients.

Calorie Restriction Slows Immune Aging in Part via Gut Microbiome Alterations

The gut microbiome and its interaction with aging is a topic of increasing interest in the scientific community. The microbial populations shift for reasons that remain unclear, becoming less helpful and more inflammatory. There is a two-way relationship between the microbiome and the immune system. Inflammatory microbes aggravate the immune system, contributing to the chronic inflammation of aging, but additionally the immune system is responsible for gardening the gut microbiome, removing problematic microbes. As the immune system fails with age, potentially harmful microbial populations can grow in size to cause greater issues.

Calorie restriction is known to improve health, slow aging, and alter the gut microbiome. It is thought that the majority of the beneficial effects of calorie restriction are mediated by upregulation of autophagy in tissues throughout the body. But is the gut microbiome also important? Today’s research materials are an example of the way in which researchers are attempting to answer that question, here by taking human microbial populations and putting them into mice, in order to see the differences pre- and post-calorie restriction.

A Low-Calorie Diet Alters the Gut Microbiome and Delays Immune Aging

Obesity increases the risk of developing high blood pressure, heart attack, or type 2 diabetes mellitus and can cause inflammation in the body that weakens the immune system through an accumulation of specific memory T cells and memory B cells. This process is called immune senescence, an age-related change in the immune system. In obese people, the development of metabolic diseases such as type 2 diabetes can be delayed by a low-calorie diet. In addition, such a diet also has a positive effect on the immune system. But exactly how the positive effects are mediated and what role the gut microbiome plays in this process is not yet known.

Researchers first analyzed how a very low-calorie diet (800 kcal/day for 8 weeks) affected the gut microbiome of an obese woman. In the next step, the researchers transplanted the gut microbiota before and after the diet intervention into germ-free mice to establish a gnotobiotic mouse model. By transplanting the diet-altered microbiota, glucose metabolism improved and fat deposition decreased. In addition, mass cytometry showed that the level of specific memory T and B cells was also reduced, indicating delayed immune senescence.

Effects of caloric restriction on the gut microbiome are linked with immune senescence

Caloric restriction can delay the development of metabolic diseases ranging from insulin resistance to type 2 diabetes and is linked to both changes in the composition and metabolic function of the gut microbiota and immunological consequences. However, the interaction between dietary intake, the microbiome, and the immune system remains poorly described.

We transplanted the gut microbiota from an obese female before (AdLib) and after (CalRes) an 8-week very-low-calorie diet (800 kcal/day) into germ-free mice. We used 16S rRNA sequencing to evaluate taxa with differential abundance between the AdLib- and CalRes-microbiota recipients and single-cell multidimensional mass cytometry to define immune signatures in murine colon, liver, and spleen.

Recipients of the CalRes sample exhibited overall higher alpha diversity and restructuring of the gut microbiota with decreased abundance of several microbial taxa (e.g., Clostridium ramosum, Hungatella hathewayi, Alistipi obesi). Transplantation of CalRes-microbiota into mice decreased their body fat accumulation and improved glucose tolerance compared to AdLib-microbiota recipients. Finally, the CalRes-associated microbiota reduced the levels of intestinal effector memory CD8+ T cells, intestinal memory B cells, and hepatic effector memory CD4+ and CD8+ T cells.

The SToMP-AD Trial of Senolytics Dasatinib and Quercetin for Alzheimer’s Disease

Accumulating evidence from animal studies indicates that senescent supporting cells in the brain (such as inflammatory microglia and astrocytes) are an important contributing cause of Alzheimer’s disease, as well as other forms of neurodegenerative condition characterized by chronic inflammation in brain tissue. There is a good chance that low-cost senolytic therapies capable of crossing the blood-brain barrier to selectively destroy some fraction of the senescent cells present in the aged brain, such as the dasatinib and quercetin combination, will turn out to be the most important Alzheimer’s therapy of the next decade or two. Clinical trials are needed to prove or disprove this hypothesis, however, and so far only a couple of projects are underway, such as the ALSENLITE and SToMP-AD trials. I had failed to notice this open access outline paper for SToMP-AD when it was published late last year, but here it is now.

Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer’s disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to control mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions.

With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer’s disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer’s disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer’s disease.

An Outline of Present Work on Partial Reprogramming as a Rejuvenation Therapy

Here I’ll point out a good, lengthy introduction to the ongoing, suddenly very well funded work on partial reprogramming as the basis for rejuvenation therapies. Reprogramming somatic cells to induced pluripotent stem cells requires exposure to the Yamanaka factors, but is a lengthy process with low efficiency. Early in that process, epigenetic patterns in a cell are restored to a more youthful configuration without the loss of differentiated somatic cell state, and this is the goal that partial reprogramming aims to achieve: restore mitochondrial function and many other cell activities in old tissues without changing cell state. Animal data is promising, even given the issues such as DNA damage that cannot be addressed by partial reprogramming, but the challenge will be how to reach this goal in a way that does not produce a significant risk of cancer via the inadvertent creation of pluripotent cells, while still rejuvenating enough of the cells in a tissue to matter.

As a whole, partial reprogramming seems quite promising: it not only improves biomarkers across tissues, but also improves aging-related functions. Even though systemic in vivo experiments of wildtype mice only showed modest outcomes so far, it might be because the protocol has not been optimized. Low hanging fruit optimizations include starting the protocol at an earlier age as well as having a longer induction period. In addition, in vivo targeted treatment in wildtype mice demonstrated impressive rejuvenation effects, implying that non-targeted and non-universal delivery may have reduced the effectiveness of in vivo systemic studies. As a result, besides protocol optimization, technology advancement in adjacent areas like gene delivery would also be required in translating partial reprogramming.

Of course, the elephant in the room is cancer risk. We have seen that partial reprogramming inevitably dedifferentiates cells. However, dedifferentiation is not always bad – if administered at the right dosage, it is reversible and won’t cause teratomas or damage to organisms. On the other hand, there are also additional efforts in finding alternative factors to the Yamanaka factors (OSKM) that are safer and more effective, both in academia and industry. It’s important to optimize what works (OSKM) and discover new factors for reprogramming rejuvenation. In this sense, it is a positive sign that half of the companies in reprogramming are focusing on optimization of OSKM and the other half are focusing on new discoveries.

Because aging is not considered a disease, it’s also important to think about what indications to pursue. Currently, skin and muscle stem cells are the two tissue types where partial reprogramming has demonstrated rejuvenation effects in both mice and humans, as well as being replicated in more than one study in the same species. Therefore, it makes sense that two out of three companies closest to clinical trials, Turn Bio and Reverse Bioengineering (AgeX), are pursuing dermatology indications. Another promising indication would be in immunotherapy, since approvals for cancer drugs are more risk tolerant than others.

Overall, we are still a long way from applying partial reprogramming to humans. Turn Bio is the company closest to clinical trials in this space (expected to start late this year) – it may take a decade for partial reprogramming to be approved for therapeutic use. Even then, there are still many challenges that need to be addressed, such as creating both universal and cell-specific gene therapy, before this technology can be used for whole body rejuvenation. In addition, partial reprogramming cannot completely reverse all the signs of aging.

Towards Partial Reprogramming to Treat Disc Degeneration

A great deal of attention is being given to partial reprogramming as a basis for regenerative therapies these days. It restores youthful gene expression in cells, and if the risk of cancer can be managed, then this may help a range of age-related degenerative conditions by improving tissue maintenance and function. Thus we should probably expect to see, in the years ahead, every narrowly focused research group produce and publish proof of concept studies that support the use of partial reprogramming for their area of interest. This happened for senolytic therapies to clear senescent cells, once that line of research was underway in earnest, and it will happen for partial reprogramming.

Rejuvenation of nucleus pulposus cells (NPCs) in degenerative discs can reverse intervertebral disc degeneration (IDD). Partial reprogramming is used to rejuvenate aging cells and ameliorate progression of aging tissue while avoiding formation of tumors resulting from classical reprogramming. Understanding the effects and potential mechanisms of partial reprogramming in degenerative discs provides insights for development of new therapies for IDD treatment.

The findings of the present study show that partial reprogramming through short-term cyclic expression of Oct-3/4, Sox2, Klf4, and c-Myc (OSKM) inhibits progression of IDD, and significantly reduces senescence related phenotypes in aging NPCs. Mechanistically, short-term induction of OSKM in aging NPCs activates energy metabolism as a “energy switch” by upregulating expression of Hexokinase 2 (HK2) ultimately promoting redistribution of cytoskeleton and restoring the aging state in aging NPCs. These findings indicate that partial reprogramming through short-term induction of OSKM has high therapeutic potential in the treatment of IDD.

Calorie Restriction and mTOR Inhibition are Additive in Slowing Muscle Loss with Age

It is intriguing to see that calorie restriction and mTOR inhibition are additive when it comes to slowing the age-related loss of muscle mass and strength, the path to sarcopenia. Both interventions are thought to influence long-term health largely through upregulation of autophagy, but calorie restriction produces very broad, sweeping changes in metabolism. The downstream changes due to mTOR inhibition only touch on a fraction of those. Thus this result may in time lead to a better understanding of which mechanisms are important in the way in which the operation of metabolism determines the pace of aging. Still, we know the scope of the benefits produced by calorie restriction in our species, and it is nowhere near as influential on life span as it is in mice. This part of the field is unlikely a path to significant gains in human longevity.

We now live longer than at any point in human history, but to enjoy those extra years, we need to remain healthy, mobile and independent. With age, however, our muscles inevitably lose mass and strength. “Age-related muscle decline already occurs in our thirties but begins to accelerate at around 60. By age 80, we have lost about a third of our muscle mass. Although this aging process cannot be stopped, it is possible to slow it down or counteract it, for example through exercise.”

Researchers have demonstrated in mice that both calorie restriction and the drug rapamycin have a positive effect on aging skeletal muscle. It was thought that moderate fasting and rapamycin represent different means of achieving the same goal, namely suppression of the protein complex mTORC1, which accelerates aging when overactive. “Contrary to our expectations, however, the treatments do not redundantly converge at mTORC1. While we could understand that calorie restriction would have beneficial effects beyond mTORC1 suppression, it was incredibly surprising to us that rapamycin, an mTORC1 inhibitor, further slowed muscle aging in calorie restricted mice, where mTORC1-activating nutrients are available for just a few hours each day.”

In calorie-restricted mice treated with rapamycin, the beneficial effects were therefore additive, with mice displaying significantly better muscle function than mice receiving either treatment alone. The positive impact of calorie-restricted diets and rapamycin on muscle aging leads to the intriguing question of whether elderly people suffering from sarcopenia can profit from a combined therapy consisting of an mTORC1 inhibitor, a calorie restriction-mimicking drug, and perhaps exercise.

High Status Actors Live Longer than their Lower Status Peers

Epidemiological data for variance in human longevity, across broad demographics, reflects a tangled web of connections between education, wealth, intelligence, and status. All of these line items correlate with one another, and there is at least some debate over why they correlate with life expectancy. For example, there is evidence for intelligence to correlate with physical robustness for genetic reasons. The data here showing that high status actors live longer than lower status actors is another piece of data that can be debated. Beyond the obvious suggestion that this is all about wealth, one can speculate on the degree to which actor status reflects a selection process that filters for greater physical robustness. The researchers here suggest the mechanism to be more subtle than either of these propositions, however, and ultimately boil down to incentives upon lifestyle choices.

We examined over two thousand actors and actresses for over 100,000 life-years of follow-up to test the association between success and survival. We found that Academy award winners live significantly longer than their co-stars. The analysis replicated earlier findings from decades ago, showed a larger difference in life-expectancy than originally reported, and suggested the increased survival extends to analyses restricted to winners and nominees. The increased life-expectancy was greater for individuals winning in recent years, at a younger age, and with multiple wins. For context, a five-year difference in life-expectancy associated with an Academy award exceeds the magnitude of lost life-expectancy for the general US population associated with the COVID-19 pandemic.

One behavioral interpretation is that social status can contribute to health in celebrities and thereby may be important more widely in society. Successful actors often have personal chefs, trainers, chauffeurs, nannies, managers, coaches, and other staff who make it easier to follow a healthy lifestyle. Academy award winners are also surrounded by people interested in their well-being, invested in their reputation, empowered to enforce standards, and motivated to avoid scandals. The result may be that winners tend to eat properly, exercise consistently, sleep regularly, avoid drug misuse, and follow the ideals of a prudent life-style that bring more gains with adherence. These behavioral mechanisms suggest social gradients in disease might be mitigated by interventions for a healthy lifestyle.

In summary, this study supports the theory that social factors may be important determinants of health at extremes of status and, therefore, might influence health for patients who have intermediate levels of success. The health effects might not be entirely due to occupation, education, or medical care. Instead, an explanation might include that successful people have more ideal lifestyles or can avoid some harmful stress.

The Merits of Late Life Suppression of Growth Hormone Signaling

The longest lived mice are those in which growth hormone or growth hormone receptor are knocked out, a gain of 70% or so in life span. They exhibit dwarfism, like the human population with the analogous inherited Laron syndrome, caused by a loss-of-function mutation in growth hormone receptor. The Laron syndrome population may be somewhat more resistant to some age-related diseases, that data still to be rigorously confirmed, but do not appear to live any longer than the rest of us. Studies on growth hormone metabolism and longevity conducted in mice should be read with that in mind, particularly when used to advocate therapeutic approaches.

One of the most potent interventions used to extend lifespan in laboratory mice is targeted disruption of the growth hormone (GH) receptor (GHR). In fact, the current record holder for the Methuselah Mouse Prize for Longevity – a mouse that lived one week shy of five years – is the GHR “knockout” (GHRKO) mouse. A new study by our laboratory suggests that partial knockdown of the GHR beginning at 6 months of age can also extend median and maximal lifespan in female mice. GH secretion decreases with age (referred to as somatopause), causing some to consider the use of GH replacement as a means to counteract aging-related conditions. Counterintuitively, diminished GH action in model organisms, either by way of natural mutations or inactivation of the GH or GHR genes, increases lifespan and slows the aging process through reducing IGF-1, mTOR signaling, and cellular senescence while simultaneously enhancing insulin sensitivity and stress resistance.

GHRKO mice (as well as most other mouse lines with reduced GH action) and humans with Laron syndrome experience the effects of the inactivated GHR gene mutations from conception; thus, the specific impact of GH on longevity in later life required further investigation. The first study was published in 2016 where we suppressed GH action at 1.5 months of age – just prior to sexual development in mice. As might be expected with GHR disruption at this younger age, mouse growth is impacted with both body weight and length significantly decreased relative to controls. Despite only partial disruption of the GHR, female 1.5mGHRKO mice have a significant increase in maximal lifespan.

We conducted a second study recently published in which GHR disruption was initiated at 6 months of age – a mature adult age in mice. Like the first study, female 6mGHRKO mice exhibit a significant extension in lifespan, but this time with mean, median, and maximal lifespan increased compared to controls. Additionally, although 6mGHRKO males did not have a significant increase in lifespan, they did have multiple signs of improved healthspan (e.g., decreased cancer, improved insulin signaling, decreased oxidative damage). Importantly, unlike the 1.5mGHRKO mice, both male and female 6mGHRKO mice have no significant changes in bodyweight and minimal impact on body length. Thus, extension in lifespan and healthspan can be achieved with GHR disruption in adult life without major changes in growth.

Collectively, these results suggest that pharmacologic modalities that block GH action later in life, even as somatopause proceeds, could have therapeutic benefit for aging and aging-related diseases. While gene disruption in humans is not viable, approved pharmacological strategies to reduce GH action exist and include somatostatin receptor ligands, dopamine agonists, and GH receptor antagonists (GHRAs). Of the options, the one that exclusively targets GH action is the GHRA, pegvisomant. This GHRA, which was discovered in our laboratory with a transgenic mouse line (GHRA mice) and approved by the FDA in 2003, is now used world-wide as a highly effective drug to antagonize GH action in the treatment of patients with acromegaly. Importantly, in a workshop convened to assess development of safe interventions to slow aging and increase healthy lifespan in humans, GHRA is cited as a promising therapeutic. Thus, when considering whether drugs designed to specifically antagonize or inhibit GH action have potential as gerotherapeutics, the current mouse study would suggest “yes”.

Age-Related Hearing Loss is Accompanied by Chronic Inflammation in the Inner Ear

Age-related neurodegeneration is strongly linked to chronic inflammation in brain tissue. Age-related hearing loss is a form of neurodegeneration, the loss of sensory hair cells in the inner ear, or the loss of the connections between those cells and the brain. Thus to find that markers of chronic inflammation in the inner ear correlate with progressive deafness is not too surprising. Ways to effectively reduce the chronic inflammation of aging should go a long way towards reducing the impact of aging on health. Senolytic therapies to remove senescent cells are the best of the present options, but more than this will be needed for complete control of inflammation in age-damaged tissues.

Age-related hearing loss (ARHL) is a major hearing impairment characterized by pathological changes in both the peripheral and central auditory systems. Low-grade inflammation was observed in the cochlea of deceased human subjects with ARHL and animal models of early onset ARHL, which suggests that inflammation contributes to the development of ARHL. However, it remains elusive how chronic inflammation progresses during normal aging in the cochlea, and especially the accompanying changes of neuroinflammation in the central auditory system.

To address this, we investigated chronic inflammation in both the cochlea and the cochlear nucleus (CN) of CBA/CaJ mice, an inbred mouse strain that undergoes normal aging and develops human, like-late-onset ARHL. Using immunohistochemistry, confocal microscopy, and quantitative image processing, we measured the accumulation and activation of macrophages in the cochlea and microglia in the CN using their shared markers: ionized calcium binding adaptor molecule 1 (Iba1) and CD68-a marker of phagocytic activity.

We found progressive increases in the area covered by Iba1-labeled macrophages and enhanced CD68 staining in the osseous spiral lamina of the cochlea that correlated with elevated ABR threshold across the lifespan. During the process, we further identified significant increases in microglial activation and C1q deposition in the CN, indicating increased neuroinflammation and complement activation in the central auditory system. Our study suggests that during normal aging, chronic inflammation occurs in both the peripheral and the central auditory system, which may contribute in coordination to the development of ARHL.

Targeting IL-9 to Reduce Perivascular Fibrosis Resulting from Hypertension

One of the more subtle forms of damage caused by the high blood pressure of hypertension is the promotion of fibrosis in the blood vessel wall, causing thickening of that structure. This is implicated in the progression of cardiovascular disease for blood vessels in the heart, particularly the microvasculature, but it causes problems elsewhere in the body as well. Here researchers demonstrate that interfering in IL-9 signaling can reverse this fibrosis to some degree. Given the behaviors of senescent cells, implicated in fibrosis, it would be interesting to see the degree to which this IL-9 signaling is a consequence of cellular senescence.

Elevated blood pressure can cause a condition known as perivascular fibrosis, where the outside wall of a blood vessel thickens due to connective tissue build-up. Although recent data has suggested that the thickening is due to the activation of T-cells, the defenders of our immune system, the underlying mechanisms are not well known. To further investigate how fibrosis develops, researchers profiled the peripheral blood mononuclear immune cells from patients with high blood pressure.

In doing so, they discovered two relevant mediators of fibrosis and potential therapeutic targets: a transcription factor, KLF10, and a cytokine, IL-9. When researchers injected mice with IL-9 neutralizing antibodies, they observed a reversal of the fibrosis and prevention of organ dysfunction, building a stronger case for targeting this pathway. “Given that hypertension contributes to a considerable number of cardiovascular-related deaths globally, we wanted to look into the depths of perivascular fibrosis for potential drug targets. We are eager to continue investigating KLF10-IL-9 signaling to hopefully create effective treatments for vascular diseases.”

Mcl-1 Inhibitors as a Novel Class of Senolytic

Researchers working with prostate cancer cells here show that senescent cancer cells depend upon Mcl-1 to prevent programmed cell death, a novel target with existing drugs that may prove useful as general purpose senolytics, able to clear senescent cells from tissues. Cancers are highly varied, and this would have to be tested against the more usual types of senescent cell present in the aged body. Even if only applicable in the context of some cancers, however, this is still a useful discovery. Cancer survivors have a significantly reduced life expectancy in large part because they suffer a greatly increased burden of cellular senescence, and thus chronic inflammation, disruption of normal tissue function, and so forth. Efficient removal of those senescent cells would be beneficial.

Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype (SASP), and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy.

Most of the currently available senotherapies for cancers are still restricted to Bcl-2 targeting. Here, we describe a population of senescent prostate cancer tumor cells that do not rely on Bcl-2 to survive. This population of cells upregulates Mcl-1 and after treatment with the Bcl-2 inhibitor Navitoclax, remains still capable to promote tumorigenesis through the SASP. Thus, regardless of senescence heterogeneity, our analysis identified Mcl-1 as a ubiquitous target to effectively remove senescent tumor cells.

We show that the efficacy of Docetaxel treatment, a standard of therapy for metastatic prostate cancer patients, can be enhanced by the concomitant administration of Mcl-1 inhibitors both in vitro and in vivo. Furthermore, treatment with different Mcl-1 inhibitors resulted in the effective removal of senescent tumor cells and the complete abrogation of the bystander migratory phenotype, orchestrated by the SASP on non-senescent tumor cells, both in transgenic and xenograft models. Moreover, this combination of compounds was superior in terms of efficacy to the combination of Docetaxel with Navitoclax.

In sum, senescent cells are highly heterogenous, but ultimately rely on a common pro-survival factor, Mcl-1. Importantly, this study endorses Mcl-1 inhibitors as a class of highly effective senolytics. Interestingly, a previous study on breast cancer showed that the senolytic sensitivity of Navitoclax is controlled by NOXA, an inhibitor of Mcl-1. While senescent cells with a high level of NOXA respond to Navitoclax, cells with a low level are resistant to Navitoclax and respond to Mcl-1 inhibitor, thereby validating our results in a different system.

The 2022 Longevity Summer Camp for People Who Want to Work in the Longevity Industry

The Less Death non-profit is founded by folk from the longevity community, with advisors that include a few of the long-standing SENS Research Foundation scientists and some of the early entrepreneurs in the longevity industry. This group is organizing a four day summer camp in June for people who want to work in the growing longevity industry. It is a good thing to make it easier to enter this part of the biotech industry, either as entrepreneurs or employees at early stage biotech companies. The focus is on education, but building a network of connections with those already involved in the industry is the real benefit to this sort of meeting.

Less Death is a nonprofit with the mission to support the growth and effectiveness of the longevity industry’s workforce. We help aspiring longevity engineers start or advance their career by providing education, career guidance, mentorship, experience, networking and employment opportunities.

While there is an emerging consensus that aging will yield to science and technology, most (if not all) currently living humans will not survive to see the post-aging future – unless progress is accelerated. The longevity industry needs more founders, scientists, engineers, programmers, lobbyists, project managers, technicians, operations and logistics experts, and many more. If you are passionate and talented, our goal is to help you find an effective way to contribute.

Join us this summer to start building a future with Less Death: a crash course on aging biology and longevity technology – with personalized advice on effective ways to contribute! Workshops by experienced longevity engineers; career strategizing inspired by Effective Altruism; mapping of critical path longevity technologies; fun and healthy longevity themed activities; building community to scale and sustain effort; career opportunities via residencies and recruiting.


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