Fight Aging!

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 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.

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Link: https://www.lessdeath.org/home#summer-camp

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.

Link: https://doi.org/10.1038/s41467-022-29824-1

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 nitrogen containing compounds within these early disease state blood samples. 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.

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."

Link: https://bwhclinicalandresearchnews.org/2022/04/21/whats-new-in-research-may-2022/

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.

Link: https://doi.org/10.3389/fnagi.2022.846804

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.

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".

Link: https://www.aging-us.com/article/204016/text

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.

Link: https://doi.org/10.7910/DVN/NBX5SJ

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).

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.

Link: https://www.unibas.ch/en/News-Events/News/Uni-Research/Multiple-treatments-to-slow-age-related-muscle-wasting.html

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.

Link: https://doi.org/10.1111/acel.13577

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.

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.

Link: https://www.adanguyenx.com/blog/partial-reprogramming

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.

Link: https://doi.org/10.14283/jpad.2021.62

If you ever want to see an earnest debate, then put a bunch of modern biogerontologists into a room and ask them to (a) define what it means to slow aging, and (b) whether or not methods known to reduce mortality and extend life in animal studies actually slow aging. You might recall the discussion a decade or so ago over whether or not mTOR inhibition, which upregulates autophagy and reliably extends life in mice, actually slows aging or just suppresses cancer incidence. Mice being little cancer factories, a reduction in cancer incidence is sufficient to move the needle on life span. A sideline to that discussion is whether or not we should consider metabolic changes that do nothing but suppress cancer incidence to count as a form of slowing aging. Data gives way to definitional wars and the drawing of lines quite quickly.

Today's open access preprint paper provides a start on generalizing this sort of discussion about the nature of aging, slowing aging, and interventions that may or may not slow aging. The authors go beyond mTOR inhibition to add other interventions that also upregulate cellular stress responses. They conclude that it is possible that age-related decline in mice is postponed rather than slowed by lifelong use of this class of intervention. The rest of us can then debate whether or not that still counts as slowing aging. As a counterpoint to this preprint, it is clearly the case that mTOR inhibition does extend remaining life span in mice when started late in life. We are left wanting more data and a greater understanding of what is going on under the hood, as usual.

Deep Phenotyping and Lifetime Trajectories Reveal Limited Effects of Longevity Regulators on the Aging Process in C57BL/6J Mice

A large body of work, carried out over the past decades in a range of model organisms including yeast, worms, flies and mice, has identified hundreds of genetic variants as well as numerous dietary factors, pharmacological treatments, and other environmental variables that can increase the length of life in animals. Current concepts regarding the biology of aging are in large part based on results from these lifespan studies. Much fewer data, however, are available to address the question of whether these factors, besides extending lifespan, in fact also slow aging, particularly in the context of mammalian models.

It is important to distinguish lifespan vs. aging because it is well known that lifespan can be restricted by specific sets of pathologies associated with old age, rather than being directly limited by a general decline in physiological systems. In various rodent species, for instance, the natural end of life is frequently due to the development of lethal neoplastic disorders: cancers have been shown to account for ca. 70-90% of natural age-related deaths in a range of mouse strains. Accordingly, there is a strong need to study aging more directly, rather than to rely on lifespan as the sole proxy measure for aging.

'Aging' is used as a term to lump together the processes that transform young adult individuals (i.e., individuals that have attained full growth and maturity) into aged ones with functional changes across multiple physiological systems, elevated risk for multiple age-related diseases, and high mortality rates. It is associated with the accumulation of a large number of phenotypic changes, spanning across various levels of biological complexity (molecular, cellular, tissue and organismal level) and affecting virtually all tissues and organ systems. Aging can hence be approached analytically by assessing age-dependent phenotypic change, from young adulthood into old age, across a large number of age-sensitive traits covering multiple tissues, organ systems and levels of biological complexity.

Here, we employed large-scale phenotyping to analyze hundreds of phenotypes and thousands of molecular markers across tissues and organ systems in a single study of aging male C57BL/6J mice. For each phenotype, we established lifetime profiles to determine when age-dependent phenotypic change is first detectable relative to the young adult baseline. We examined central genetic and environmental lifespan regulators (putative anti-aging interventions, PAAIs; the following PAAIs were examined: mTOR loss-of-function, loss-of-function in growth hormone signaling, dietary restriction) for a possible countering of the signs and symptoms of aging. Importantly, in our study design, we included young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. In parallel to our studies in mice, we assessed genetic variants for their effects on age-sensitive phenotypes in humans.

We observed that, surprisingly, many PAAI effects influenced phenotypes long before the onset of detectable age-dependent changes, rather than altering the rate at which these phenotypes developed with age. Accordingly, this subset of PAAI effects does not reflect a targeting of age-dependent phenotypic change. Overall, our findings suggest that comprehensive phenotyping, including the controls built in our study, is critical for the investigation of PAAIs as it facilitates the proper interpretation of the mechanistic mode by which PAAIs influence biological aging.

Researchers here note the interactions between the cellular maintenance processes of autophagy and cellular senescence. Upregulated autophagy can prevent cells from falling into the senescent state, observed in the use of mTOR inhibitors, for example. Once a cell is senescent, either sabotaging or increasing autophagy can destroy it, or at least make it more vulnerable to senolytic treatments that provoke programmed cell death. Regardless, small molecule therapies that upregulate autophagy in every cell they can reach would still likely be beneficial even in people with a high burden of senescent cells. The immune system of an older individual still clears senescent cells, just slowly, and thus reducing the number of new cells that become senescent in the age-damaged tissue environment can allow clearance to catch up over time.

The relationship between cellular senescence and autophagy is regarded as paradoxical. Autophagy activation in response to stress can successfully resolve it and thus spare the cell from entering senescence. However, if a cell does commit to senescence by other ways, autophagy becomes essential for cell survival and senescence establishment. Indeed, senescence-associated secretory phenotype (SASP) production imposes its burden on the secretory pathway, calling for increased proteostasis maintenance. In this regard, the first-ever demonstration of selective pharmacological elimination of senescent cells consisted in depriving therapy-induced senescent lymphoma of adaptive autophagy, leading to proteotoxic stress overload due to SASP expression.

Senolysis can actually be achieved by modulating autophagy in either direction: inhibiting autophagy can lead to proteotoxic stress in senescent cells producing an abundant SASP, and conversely, further activating autophagy can selectively kill senescent cells through type II autophagic cell death, i.e. excessive "self-eating".

Beyond bulk autophagy flux modulations to cope with increased secretory demands, finer processes appear to be at play in regulating proteostasis in senescence. Recently, it was shown that the stability of a defined set of proteins was regulated by selective autophagy in senescence through differential interactions with ATG8 family receptors. This selective autophagy network was fundamental in shaping several facets of the senescent phenotype, including SASP production and proteostasis. These studies pave the way for a more precise understanding of autophagy regulation in the physiology and the proteostasis of senescent cells, and the discovery of potentially more potent senolytic strategies.

Link: https://doi.org/10.18632/aging.203941

Partial reprogramming of cells to restore youthful epigenetic patterns, and thus gene expression, is becoming quite the popular field of development. Based on results in mice, it is thought that the in vivo application of the Yamanaka factors could be made safe enough to be the basis for practical whole-body rejuvenation therapies. While epigenetic reprogramming can't do much for DNA damage and some of the persistent molecular waste found in old tissues, among other issues, it has been shown to restore lost mitochondrial function. It may ameliorate a range of other issues as well, and could prove to be beneficial enough to justify the present sizable investment into research and development, largely centered on Altos Labs. Funding attracts attention, and many others are joining in, with YouthBio Therapeutics being the latest new biotech company to throw its hat into the ring.

YouthBio Therapeutics, a longevity biotechnology company, has announced today its emergence out of stealth mode. YouthBio focuses on developing gene therapies aimed at epigenetic rejuvenation, particularly with the help of partial reprogramming by Yamanaka factors. The company was founded in early 2021 by Yuri Deigin and Viet Ly who will serve as its CEO and CFO, respectively. Dr. João Pedro de Magalhães will serve as the company's CSO and Dr. Alejandro Ocampo will serve as lead research collaborator.

"I am very optimistic that in the next 10 years science will provide humanity with major breakthroughs that will enable us to add decades of healthy life to people. Partial reprogramming is something I was always excited about as having the potential to be one such therapy. I am thrilled to take its research and development to the next level with the help of amazing colleagues."

"Cellular reprogramming allows us to rejuvenate cells and reset their biological clocks. It is the most important technology available today for developing rejuvenation therapies, although it still needs to be fine-tuned for effective and safe applications. Exploiting cellular reprogramming to develop therapies for age-related diseases is extremely exciting and, if successful, may result in a paradigm shift in medicine."

Link: https://www.prnewswire.com/news-releases/youthbio-therapeutics-exits-stealth-mode-301525511.html

Neurogenesis is assessed in the hippocampus in most studies, connected to the processes of memory. Neurogenesis is the production of new neurons from neural stem cells and their integration into existing neural circuits. The areas of the brain responsible for memory must change, but it is an open question as to how much neurogenesis is going on elsewhere, and particularly in the adult human brain, where studies are far more limited than is the case for mice.

Increased neurogenesis is thought to be generally beneficial to cognitive function at all ages, and it may be an important mechanism by which, for example, exercise improves memory and other capabilities. Beyond this, sizable increases in neurogenesis may be a path towards better maintenance of the aging brain, and recovery from injury, though this is more of an open question at the present time.

Thus approaches capable of increasing neurogenesis are of interest to those of us who would like to be less impacted by the processes of aging. As yet, doing better than exercise is challenging, given the classes of mechanism and approach that are most explored. On the one hand, exercise and the production of butyrate by the gut microbiome lead to upregulation of BDNF, which promotes neurogenesis. On the other hand, SSRIs as a class of drug are known to increase neurogenesis, though with side-effects that make them undesirable for general use. In today's research materials, researchers find a way to trigger a regulator of neural stem cell activity, which may prove to be the basis for new classes of therapy that more directly increase neurogenesis.

Oleic acid, a key to activating the brain's 'fountain of youth'

Years ago, scientists thought that the adult mammalian brain was not able to repair and regenerate. But research has shown that some brain regions have the capacity of generating new neurons, a process called neurogenesis. The hippocampus region of the adult mammalian brain has the ongoing capacity to form new neurons, to repair and regenerate itself, enabling learning and memory and mood regulation during the adult life.

'We knew that neurogenesis has a 'master regulator,' a protein within neural stem cells called TLX that is a major player in the birth of new neurons. We did not know what stimulated TLX to do that. Nobody knew how to activate TLX. We discovered that a common fatty acid called oleic acid binds to TLX and this increases cell proliferation and neurogenesis in the hippocampus of both young and old mice."

While oleic acid also is the major component in olive oil, however, this would not be an effective source of oleic acid because it would likely not reach the brain. It must be produced by the cells themselves. The finding that oleic acid regulates TLX activation has major therapeutic implications. "TLX has become a 'druggable' target, meaning that knowing how it is activated naturally in the brain helps us to develop drugs capable of entering the brain and stimulating neurogenesis."

Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis

Neural stem cells, the source of newborn neurons in the adult hippocampus, are intimately involved in learning and memory, mood, and stress response. Despite considerable progress in understanding the biology of neural stem cells and neurogenesis, regulating the neural stem cell population precisely has remained elusive because we have lacked the specific targets to stimulate their proliferation and neurogenesis. The orphan nuclear receptor TLX/NR2E1 governs neural stem cell and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is not well understood because its endogenous ligand is not known.

Here, we identify oleic acid as such a ligand. We first show that oleic acid is critical for neural stem cell survival. Next, we demonstrate that it binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell-cycle and neurogenesis genes, which in turn increases neural stem cell mitotic activity and drives hippocampal neurogenesis in mice. Interestingly, oleic acid-activated TLX strongly up-regulates cell cycle genes while only modestly up-regulating neurogenic genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation and drive the progeny toward neuronal lineage. Oleic acid thus serves as a metabolic regulator of TLX activity that can be used to selectively target neural stem cells, paving the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.

The aging of hematopoietic stem cells is an important contributing factor in the decline of the immune system in later life, resulting in reduced clearance of senescent cells and pathogens, alongside increasing chronic inflammation. One of the problems deriving from impaired hematopoiesis is that the production of immune cells becomes skewed towards myeloid lineages, biasing the immune system towards the above mentioned declines. There are a range of potential approaches that might help with these issues, from introducing new hematopoietic stem cells to suppressing chronic inflammation to small molecules that may favorably adjust the behavior of native cells. Age-related dysfunction of hematopoiesis isn't a simple challenge, however, as stem cell function depends on the supporting cells of the stem cell niche and the systemic signaling environment, rather than only on the integrity of the stem cell population itself.

There is a hot topic in stem cell research to investigate the process of hematopoietic stem cell (HSC) aging characterized by decreased self-renewal ability, myeloid-biased differentiation, impaired homing, and other abnormalities related to hematopoietic repair function. It is of crucial importance that HSCs preserve self-renewal and differentiation ability to maintain hematopoiesis under homeostatic states over time. Although HSC numbers increase with age in both mice and humans, this cannot compensate for functional defects of aged HSCs.

The underlying mechanisms regarding HSC aging have been studied from various perspectives, but the exact molecular events remain unclear. Several cell-intrinsic and cell-extrinsic factors contribute to HSC aging including DNA damage responses, reactive oxygen species (ROS), altered epigenetic profiling, polarity, metabolic alterations, impaired autophagy, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, nuclear factor- (NF-) κB pathway, mTOR pathway, transforming growth factor-beta (TGF-β) pathway, and wingless-related integration site (Wnt) pathway.

To determine how deficient HSCs develop during aging, we provide an overview of different hallmarks, age-related signaling pathways, and epigenetic modifications in young and aged HSCs. Knowing how such changes occur and progress will help researchers to develop medications and promote the quality of life for the elderly and possibly alleviate age-associated hematopoietic disorders. The present review is aimed at discussing the latest advancements of HSC aging and the role of HSC-intrinsic factors and related events of a bone marrow niche during HSC aging.

Link: https://doi.org/10.1155/2022/2713483

A cure for aging, as presently envisaged, would be a matter of bringing aging under medical control. Not stopping its progression, but rather periodically repairing the damage that accumulates in tissues as a result of the normal operation of metabolism. Present goals in the longevity industry are largely unambitious, aimed at a very modest improvement over the present situation via adjustment of metabolism, such as via mimicking some of the effects of calorie restriction. Thus more advocacy for the better end goal is necessary. More persuasion! There are approaches that can repair the molecular damage of aging, such as senolytic therapies to remove senescent cells, and other less well developed line items from the SENS program for rejuvenation therapies. Advancing the state of the art in this part of the field should be the priority.

The ultimate goal should be to "cure aging" - a phrase that many in the field are uncomfortable with. "What I mean by curing aging is having a risk of death that doesn't vary depending on how long ago you were born. A lot of scientists, even aging biologists, get a little bit squeamish when you say that. But I really do think that should be the fundamental aim of all medicine."

Using cancer as an example, most scientists working in that field would agree they are working towards an end goal of curing cancer. "I don't see why aging should be any different. At least the aspects of aging that cause frailty and discomfort and distress and pain and disease and all these horrible things we want to get rid of. I don't see why our goal shouldn't be to minimise that human suffering as far as possible. And to me, that means curing aging."

"How possible is that going to be? I'm absolutely convinced it's possible at some point. There's no law of biology that tells us we must age - we can look around the animal kingdom and see animals that don't age, they're negligibly senescent, they have exactly this risk of death that doesn't vary depending on how long ago they were born. The real question is, are we clever enough? Is our biotechnology advanced enough? And are we going to get lucky enough that it's going to happen in our generation?"

Link: https://www.longevity.technology/andrew-steele-our-goal-must-be-to-cure-aging/

In today's open access research, scientists demonstrate that mice lacking FGF21 do not benefit from protein restriction, a dietary intervention that usually produces slowed aging and extended life span in that species. FGF21 has been the subject of a fair amount of attention from the research community in the context of aging in recent years, attention drawn to this gene because it is upregulated by the practice of calorie restriction, as well as by protein restriction. Artificially increasing FGF21 expression via genetic engineering has been shown to extend life in mice.

Like many aspects of cellular biochemistry altered by calorie restriction, FGF21 influences many very fundamental cellular behaviors, such as regulation of growth. Further, it is involved in higher level systems such as insulin metabolism, mitochondrial function, and immune activity. This makes it a little challenging to determine the degree to which it is important, or which of its activities are important. This is a common issue in the response to calorie restriction. Showing that FGF21 knockout prevents extended life resulting from protein restriction, and then tracing some of the downstream differences, is a step towards a better understanding of the very complex, sweeping changes that take place in response to a reduced intake of protein or calories.

FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice

A variety of dietary interventions (i.e., calorie restriction, intermittent fasting, fasting mimetics, and dietary restriction) improve health and lifespan. Epidemiological data suggest that lowering dietary protein content supports metabolic improvements and resilience, while high protein intake correlates with increased mortality. Protein restriction (PR) is a form of dietary restriction in the absence of energy restriction that extends lifespan and improves general health measures in various organisms, including rodents, fruit flies, and yeast.

The PR-induced improvements on health naturally create an interest in the underlying cellular mechanisms. Most work has accentuated the ability of protein or amino acid restriction to engage a host intracellular nutrient-sensing pathways, including mTOR, GCN2, AMPK, autophagy, etc. However, several years ago our lab hypothesized that an endocrine effector signal of protein restriction might exist. This focus led to the discovery that the liver-derived hormone FGF21 is robustly induced by PR and that the deletion of FGF21 blocks adaptive metabolic responses to PR in young mice.

FGF21 increases energy expenditure, enhances glucose metabolism, and upregulates the thermoregulatory marker UCP1. FGF21 also crosses the blood-brain barrier, and several studies suggest that the physiological effects of FGF21 are mediated by the brain. Recent data from our lab indicate that FGF21/Klb signaling in the brain is essential for PR to increase energy expenditure, improve glucose homeostasis, and protect against diet-induced obesity in young mice.

Factoring in FGF21's key role in facilitating the metabolic response to PR in young mice, and that transgenic overexpression of FGF21 extends lifespan and improves insulin sensitivity, we hypothesized that increases in FGF21 might mediate the beneficial effects of long-term PR in aging animals. Here we demonstrate that, in male mice, FGF21 is required for the effects of PR on lifespan and metabolism. Indeed, mice that are FGF21 deficient are not only resistant to the health benefits effects of PR, but they also exhibit early-onset weight loss, increased frailty, and reduced lifespan when fed a low protein diet. Collectively, these data represent a suggest that FGF21 is essential for the pro-longevity effects of PR and highlight the power of a single endocrine hormone to coordinate metabolic and behavioral responses that improve metabolism and longevity.

Killifish are one of the species capable of scar-free regeneration of organs following injury, a capability that researchers suspect exists in humans and other mammals, suppressed after early development, but accessible given the right manipulation of genetic controls, yet to be discovered. The study here notes that killifish appear to lose this capability in later life. Having a species that exhibits both proficient and limited regeneration under different circumstances may point the way towards specific genes and mechanisms relevant to the goal of enabling proficient regeneration in human patients. Or it may be entirely irrelevant to inter-species differences, a peculiarity unique to killifish. The only way to find out is to follow the thread and see where it leads.

Over the recent years, the fast-aging African turquoise killifish (Nothobranchius furzeri) has emerged as an excellent biogerontology model, Despite having a lifecycle of only a few months, killifish do age. They even age in a similar way as humans, presenting many of the well-described aging hallmarks, yet often magnified and occurring within a much shorter time frame. Interestingly, killifish appear to pay a price for their fast growth and aging. In contrast to zebrafish - that maintain their neuroreparative ability albeit regenerate less efficiently at old age - killifish completely lose their regeneration capacity at old age and are unable to fully recover from central nervous system (CNS) injury.

Using an optic nerve crush injury model in killifish of different ages, we indeed revealed that, in contrast to young fish, aged animals do not regain vision following damage. An inadequate intrinsic capacity of aged retinal ganglion cells (RGCs) to revert to a "regenerative state" as well as a growth-inhibiting neuron-extrinsic environment seem to contribute to this impairment, similar to what has been described for (young) adult mammals. We postulate that age-associated changes within neurons and their glial environment - already manifesting before damage occurs- negatively affect the regeneration potential of the killifish CNS, which then leads to a mammalian-like regenerative response upon injury.

With increasing age, we revealed reduced expression levels of growth-associated genes in retinal neurons, thereby affecting the intrinsic ability of RGCs to regrow their axons. Additionally, oxidative stress was shown to pile up in the aged killifish retina, which is known to lead to mitochondrial dysfunction and therefore very likely contributes to failure of the energy-demanding regenerative process. Next to neuron-intrinsic changes, we observed signs of astrogliosis, inflammaging, and a senescence-associated secretory phenotype upon aging, which might sensitize the old killifish CNS and result in growth-unfavorable glial reactivity upon injury.

The onset of astrogliosis and a chronic inflammatory status in the killifish CNS during physiological aging seems to result in a more extensive and extended glial reactivity upon nerve injury, which is known to be detrimental for regeneration in mammals. Strikingly, the exaggerated neuroinflammatory events then result in the formation of a long-term glial scar. In summary, it seems that explosive growth and/or fast aging eventually turns the killifish CNS into a regeneration-incompetent organ. By shifting its regenerative potential from high to low with increasing age and forming a glial scar following CNS injury, the killifish puts itself in the exceptional position of resembling (young) adult mammals when at old age.

Link: https://doi.org/10.18632/aging.203995

Cells signal to one another in a variety of means, and a large fraction of those signals pass back and forth in extracellular vesicles, small membrane-wrapped packages of molecules. An interesting use of extracellular vesicles is demonstrated here, delivering signals that provoke greater muscle regrowth in old mice than would otherwise be the case. Since it also works in young mice, this may be a basis for an enhancement therapy for people of all ages interested in building muscle. Extracellular vesicles can be harvested from cells and used in therapy more cost-effectively than the use of cell transplants. Thus much of the research community is engaged in various forms of the move from delivering cells to delivering vesicles harvested from those cells.

Scientists have developed a promising new method to combat the age-related losses in muscle mass that often accompany immobility after injury or illness. Physical therapy is often prescribed to promote healing after injury and immobility, she said. But studies show that muscle continues to deteriorate after the onset of exercise. Reactive oxygen species, a signal of inflammation and cellular dysfunction, accumulate in the muscles and impede the healing process.

In a previous study, researchers discovered that injections of support cells known as pericytes contributed to muscle recovery in young mice after a period of immobility. However, aged mice did not respond as well to the injections, and recovery was limited. In the new study, the team collected pericytes from the muscles of young, healthy mice and grew them in cell culture. They exposed the cells to hydrogen peroxide - a powerful oxidant that promotes the production of extracellular vesicles (EVs) containing factors that combat stress and enhance healing - and collected the EVs to use therapeutically.

The researchers injected their pericyte-derived EVs into the muscles of young and aged mice that had undergone a period of prolonged muscle immobility in one of their legs and were beginning to use those muscles again. The approach worked: The mice treated with the stimulated EVs recovered skeletal muscle fiber size in both young and aged mice. The study also revealed - for the first time - that EVs derived from muscle pericytes produced a variety of factors that may combat inflammation and oxidative stress.

Link: https://news.illinois.edu/view/6367/1107069392

The immune system is a very complex, self-regulating system. In youth, it becomes inflamed in response to injury or pathogens, and that inflamed state is resolved once the immediate need is met. There are many pathways to rousing the immune system to inflammation, and some of these malfunction or are inappropriately stimulated in later life as a result of molecular damage, excess visceral fat tissue, senescent cell signaling, and so forth. This leads to chronic inflammation, overwhelming the equally diverse set mechanisms that are responsible for resolving inflammation after it has served its purpose.

Inflammation is important enough in aging and age-related disease to be a prominent target for therapies. Treatments to date have focused on bluntly sabotaging inflammatory signals that have been identified as important, which impairs necessary inflammation even as it reduces excessive inflammation to some degree. Since there are many such pathways to block, most of which are needed for the immune system to serve its purpose in defending the body, it may be that a better path forward is to strengthen the natural mechanisms responsible for resolving inflammation. Hence today's research materials, looking into how the immune system and nervous system interact via well-studied neurotransmitters. As this relationship is better understood, methods may emerge to intervene in order to more naturally reduce chronic inflammation.

Immune cells produce chemical messenger that prevents heart disease-related inflammation

The immune system's white blood cells, which are produced in the bone marrow, mostly help to defend against bacteria and injury, but sometimes they can turn against the body - for example, in cardiovascular disease, their inflammatory aggression can harm arteries and the heart. The nervous system plays a role in controlling blood cell production through chemical messengers or neurotransmitters. This is important in people exposed to stress, where stress hormones controlled by the sympathetic nervous system may increase bone marrow activity and cardiovascular inflammation in response to the neurotransmitter noradrenaline. The sympathetic nerves have a counter player - the parasympathetic nerves, which slow down responses and bring about a state of calm to the body, mainly through the neurotransmitter acetylcholine.

Because acetylcholine can have a protective effect against inflammation and heart disease, researchers studied this neurotransmitter in the bone marrow. "When we looked into how acetylcholine acts on the production of blood cells, we found that it does the expected - it reduces white blood cells, as opposed to noradrenaline, which increases them. What was unexpected though was the source of the neurotransmitter acetylcholine." The team found no evidence in the bone marrow of the typical nerve fibers that are known to release acetylcholine. Instead, B cells, which are themselves a type of white blood cell (most known for making antibodies), supplied the acetylcholine in the bone marrow. "Thus, B cells counter inflammation-even in the heart and the arteries - via dampening white blood cell production in the bone marrow. Surprisingly, they use a neurotransmitter to do so."

B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis

Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor+ (LepR+) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease.

The heart is of interest to a great many groups working on implementations of regenerative medicine, particularly in the context of alleviating the consequences of a heart attack. The scarring and damage of a heart attack can lead to ultimately fatal forms of arrhythmia, among other issues. Here, researchers discuss an exosome therapy approach to regenerating the damaged heart in order to address arrhythmia. Considerable progress has been made in recent years to adapt cell therapy approaches to the easier, more manageable use of exosomes derived from those cells. The exosomes carry signals that alter native cell behavior in much the same way as do transplanted cells. In most cell therapies the majority of the effect is due to signaling, not due to any work carried out by the cells introduced into the patient.

Ventricular arrhythmia­s can occur after a heart attack damages tissue, causing chaotic electrical patterns in the heart's lower chambers. The heart ends up beating so rapidly that it cannot support the circulation, leading to a lack of blood flow and, if untreated, death. Current treatment options for ventricular arrhythmia­s caused by heart attacks are far from ideal. These include medications with major side effects, implanted devices to provide an internal shock, and a procedure called radiofrequency ablation in which parts of the heart are purposely destroyed to interrupt disruptive electrical signals. Recurrence rates are, unfortunately, high for all of these.

Researchers sought to try a different approach in laboratory pigs that experienced a heart attack. They injected some of the laboratory pigs with tiny, balloon-like vesicles, called exosomes, produced by cardiosphere-derived cells (CDCs), which are progenitor cells derived from human heart tissue. Exosomes are hardy particles containing molecules and the molecular instructions to make various proteins, thus they are easier to handle and transfer than the parent cells, or CDCs. The animals were evaluated by MRI and tests to assess electrical stability of the heart. Four to six weeks after injection, the laboratory pigs that had received the exosome therapy showed markedly improved heart rhythms and less scarring in their hearts.

Link: https://www.cedars-sinai.org/newsroom/cell-derived-therapy-may-help-repair-abnormal-heart-rhythm/

The relationship between low dose lithium intake and slowed aging is an interesting one, through not of any practical value given that the effect size is small, where rigorously tested in animal studies. It is visible in human epidemiology thanks to differing levels of lithium in the water supply. Researchers here suggest that this relationship is mediated by a slowing of the age-related decline in kidney function. Loss of kidney function is harmful to organs throughout the body, and it is worthy of note that one of the better studied longevity genes, klotho, appears to function via protection of kidney function in aging.

Kidney function tends to decline as people age, by as much as 50%, even in the absence of any identifiable kidney disease. This can be an important health issue for many elderly patients, increasing their risk of developing kidney failure and complicating treatment of many other medical conditions.

While lithium is a highly effective mood stabilizer and first-line treatment for bipolar disorder, scientists still don't know exactly how it works in the brain. However, researchers have found that one of the major molecular targets of lithium is GSK3-beta - an enzyme that is associated with cellular aging in the kidney and a decline in kidney function.

Researchers demonstrated that knocking out the gene responsible for producing GSK3-beta slowed kidney aging and preserved kidney function in animal models. Researchers then used lithium chloride to inhibit GSK3-beta, which achieved similar results. Mice had lower levels of albuminuria, or protein in the urine, improved kidney function and less cellular deficiency compared to a control group.

To further validate their findings, researchers also reviewed a group of psychiatric patients to assess their kidney health. Laboratory tests showed individuals who had received long-term treatment with lithium carbonate had better functioning kidneys than those who had not received lithium treatments, despite comparable age and comorbidities.

Link: https://www.eurekalert.org/news-releases/949463

Senescent cells accumulate with age in all tissues, an imbalance between the pace of creation, accelerated due to the damaged tissue environment, and the pace of clearance by the immune system, slowed for a range of reasons related to the age-related decline in immune function. This accumulation is harmful, as senescent cells generate an inflammatory mix of signals, the senescence-associated secretory phenotype (SASP). Sustained over the long term, the SASP contributes to chronic inflammation and many forms of tissue dysfunction, leading into age-related disease.

Osteoporosis, the loss of bone density and strength that takes place with age, is one of the many inflammation-linked conditions in which senescent cells are thought to play a meaningful role. The extracellular matrix of bone tissue, providing its structural properties, is constantly remodeled. At root osteoporosis is another form of imbalance, between the activities of osteoblast cells that create the matrix and osteoclast cells that break down the matrix. Beneath that simple summary lies a great deal of complexity and debate over the relevance of one mechanism over another, however. In today's open access paper, researchers tour a number of these debated mechanisms in the context of the presence of senescent cells and their inflammatory, disruptive signaling.

Crosstalk Between Senescent Bone Cells and the Bone Tissue Microenvironment Influences Bone Fragility During Chronological Age and in Diabetes

Bone is a complex organ serving roles in skeletal support and movement, and is a source of blood cells including adaptive and innate immune cells. Structural and functional integrity is maintained through a balance between bone synthesis and bone degradation, dependent in part on mechanical loading but also on signaling and influences of the tissue microenvironment. Bone structure and the extracellular bone milieu change with age, predisposing to osteoporosis and increased fracture risk, and this is exacerbated in patients with diabetes. Such changes can include loss of bone mineral density, deterioration in micro-architecture, as well as decreased bone flexibility, through alteration of proteinaceous bone support structures, and accumulation of senescent cells.

Senescence is a state of proliferation arrest accompanied by marked morphological and metabolic changes. It is driven by cellular stress and serves an important acute tumor suppressive mechanism when followed by immune-mediated senescent cell clearance. However, aging and pathological conditions including diabetes are associated with accumulation of senescent cells that generate a pro-inflammatory and tissue-destructive secretome (the SASP). The SASP impinges on the tissue microenvironment with detrimental local and systemic consequences; senescent cells are thought to contribute to the multimorbidity associated with advanced chronological age.

Here, we assess factors that promote bone fragility, in the context both of chronological aging and accelerated aging in progeroid syndromes and in diabetes, including senescence-dependent alterations in the bone tissue microenvironment, and glycation changes to the tissue microenvironment that stimulate RAGE signaling, a process that is accelerated in diabetic patients. Finally, we discuss therapeutic interventions targeting RAGE signaling and cell senescence that show promise in improving bone health in older people and those living with diabetes.

Inflammatory behavior of the innate immune cells known as microglia is strongly implicated in age-related neurodegeneration. Some microglia are senescent, others just overactive, but the result is chronic inflammation in brain tissue. This situation can be improved in animal models by clearing microglia, but while the means of doing this are readily available, existing drugs that could be repurposed to treat neurodegenerative conditions, such as the senolytic combination of dasatinib and quercetin, or the CSF1R inhibitor PLX3397, clinical trials are yet to run. Researchers here note the connection between the age-related changes of the gut microbiome, which encourage inflammation, and the inflammatory behavior of microglia. Intervening to restore a more youthful gut microbiome is another line of work that is a practical possibility, with several methods demonstrated in animal studies and easily applied to humans, such as flagellin immunization or fecal microbiota transplantation, but yet to reach clinical trials.

Microglia are a group of neuroglia that account for 5-15% of total brain cells. As the resident-macrophage cells, microglia function as the main immune defense in the central nervous system (CNS). To sustain brain homeostasis, microglia continually surveille the brain microenvironment through their connections with neighboring cells and factors. During aging, microglia switch from resting state to activated state and contribute to the development of neurogenerative diseases. Activated microglia produce pro-inflammatory cytokines, and participate in regulating blood-brain barrier (BBB) integrity and synaptic plasticity in aged brain.

Recent studies suggested that the alterations of gut microbiota in the aged are associated with neurodegenerative diseases. Gut-brain axis indicates the complicated connections between gut and brain, which is crucial for microglial maturation and function. These findings pave a new way in attenuating and even reversing cognitive aging through microbiota-microglia axis intervention. In this review, we will review the composition of gut microbiota in aged individuals, depict the changes of microglia associated with aging and discuss neuroinflammation in the aged brain. We then summarize the mechanism of microbiota in regulating microglial function in the aged brain and highlight the role of microbiota-microglia connections in neurodegenerative diseases. This knowledge may enrich our understanding of the crosstalk between aging-related cognitive decline and the microbiota-microglia axis, facilitating the discovery of novel targets in restoring aging-related cognitive decline.

Link: https://doi.org/10.1111/acel.13599

Researchers have spent a great deal of effort looking for genetic determinants of longevity in long-lived families. Elsewhere, initiatives searching large national databases for genetic determinants of longevity have turned up increasing evidence for genetic variations to play very little role in human life span. The pendulum is swinging towards the idea that the specifics of culture within human lineages are largely responsible for differences in longevity: who stays thin; who exercises; who maintains beneficial dietary habits; who has a lesser early life exposure to persistent pathogens; and so forth.

What makes some people predisposed to live and remain healthy much longer than others? That some persons reach an exceptional age has been recorded throughout history. It's tempting to write down such outliers as only the result of environment and behavior: for example, better-than-average nutrition, medical care, childcare practices, and hygiene, not to mention luck. But as average life expectancy continues to increase worldwide due to overall improvements in these and other factors, it's becoming clear that exceptional longevity and healthy aging tends to run in families. This suggests that genetic differences also play a role in assuring lifespan and life-long good health.

The Long Life Family Study (LLFS) focuses on families in the US and Denmark with multiple exceptionally long-lived members. It identifies, across two generations, which genetic, epigenetic, and other biological processes are associated with long life and healthy aging. Researchers now show that children born in exceptionally long-lived families differ from peers in their blood levels of biomarkers affecting the risk of type II diabetes: their genetic and epigenetic make-up help their body to remain responsive to insulin, even in old age. Their spouses - typically not born to exceptionally long-lived parents - tend to share these health- and lifespan-boosting biomarker levels. This implies that such family-specific beneficial biomarker levels aren't always inherited - you might also develop them if married to the right partner.

Among the children and their spouses, respectively 3.7% and 3.8% developed type II diabetes over the course of the study. This corresponds to a rate of 4.6 to 4.7 new cases of type II diabetes per 1000 person-years, about 53% lower than the rate among people between 45 and 64 years in the general US population. This implies that both the children and their spouses had a reduced risk of developing type II diabetes: one of the health and longevity benefits of being part of a long-lived family, either through descent or marriage.

Link: https://www.eurekalert.org/news-releases/949408

Methionine restriction produces benefits to health and longevity in animal studies. This involves minimizing the dietary intake of the essential amino acid methionine while maintaining all of the other necessary nutrients. Much of the nutrient sensing that alters downstream cellular activities in response to a lower intake of calories is based upon assessment of methionine levels. Thus methionine restriction without calorie restriction triggers a sizable fraction of the same beneficial upregulation of cell maintenance processes, leading to improved tissue function, slowed aging, and so forth.

In comparison to the practice of calorie restriction, achieving a meaningful degree of methionine restriction, without reducing calories, is a harder dietary undertaking. The publicly available data on methionine levels is of poor quality and far from complete. Near all staple food choices contain a lot of methionine. There are medical diets manufactured with low methionine levels, used to treat a few uncommon conditions, but they are neither easily obtained nor easily reverse engineered. These issues could be bypassed given a suitable business venture focused on manufacturing such a diet for the public rather than for patients, but it is unclear that producing low methionine foods outside the medical diet industry is in any way commercially viable.

Thus we come to whether or not methionine-based nutrient sensing can be triggered by other means. In today's open access paper, researchers take a look at one of the options on the table. Memetics will never be as good as the real thing, but it is in principle possible that any given mimetic could be good enough to merit time and effort on the part of the research community. Certainly, the quality of calorie restriction mimetics varies widely, and we might expect the same to be true of methionine restriction mimetics.

S-adenosyl-L-homocysteine extends lifespan through methionine restriction effects

Dietary restriction, including methionine restriction (MetR) , is an effective strategy for promoting longevity and counteracting age-related morbidities. In addition, genetic manipulation or pharmacological inhibition of methionine (Met) metabolic pathways and a Met-restricted diet prolong lifespan. Several studies indicate that a MetR diet is possible for humans, but long-term compliance to such a diet is considered problematic. Previously, we showed that a yeast mutant that accumulates S-adenosyl-L-methionine (SAM) to high levels exhibited reduced intracellular Met and lifespan extension mediated through AMPK activation. We also showed that in a wild-type (WT) strain, supplementation with S-adenosyl-L-homocysteine (SAH) increased SAM levels, activating AMPK, and extending lifespan.

To investigate the basis for SAH-mediated longevity, we performed metabolomics analysis of a WT yeast strain. As previously reported, SAH administration increased levels of SAH and SAM, a methyl group donor. SAH is a potent competitive inhibitor of SAM-dependent methyltransferases, and SAH accumulation thereby impairs cell growth. we speculate that SAH supplementation can increase SAM synthesis through an unknown mechanism. Since SAM synthesis requires Met, stimulating SAM production can decrease the quantity of intracellular Met. Notably, among the amino acids, Met exhibited significantly reduced levels after SAH supplementation.

The lower Met content in SAH-treated cells suggests that longevity from SAH supplementation can induce a MetR state. Hence, since MetR extends chronological lifespan (CLS) in an autophagy-dependent manner, we investigated the effect of SAH on autophagy. SAH treatment increased degradation of an autophagy marker, suggesting that SAH administration promotes autophagy.

Subsequently, to determine whether SAH acts as an anti-aging metabolite in a metazoan, we investigated its effects on the nematode C. elegans. SAH treatment extended the lifespan of WT animals in a concentration-dependent manner,. Notably, SAH did not affect food consumption, brood size, or viability. SAH also partially prevented the aging-associated decrease in physical capacity. Altogether, these results suggest that SAH mediates phylogenetically conserved anti-aging effects.

In conclusion, our results suggest that SAH extends lifespan by inducing MetR or mimicking its downstream effects. Since the lifespan-extending effects of SAH are conserved in yeast and nematodes, and MetR extends the lifespan of many species, exposure to SAH is expected to have multiple benefits across evolutionary boundaries. Our findings offer the enticing possibility that in humans the benefits of a MetR diet can be achieved by promoting Met reduction with SAH. The use of endogenous metabolites, such as SAH, is considered safer than drugs and other substances, suggesting that it may be one of the most feasible ways to prevent age-related diseases.

An interesting commentary here notes the extended life span in flies that results from the upregulation of the Mask gene in dopaminergenic neurons only. This is accompanied by extended reproductive life span as well, indicating an overall improvement in health along with extended life. In short-lived species there are many examples of this sort of single gene alteration that results in overall improvement, demonstrating that the processes of evolution do not optimize for life span. Should we expect to find analogous single gene alterations in humans? That question is complicated by the fact that long-lived species such as our own exhibit life spans that are much less plastic in response to metabolic and environmental factors when compared to the life spans of short-lived species. Mice can live 40% longer in response to calorie restriction, 70% longer in response to growth hormone receptor knockout, but in humans neither of those states appears to result in more than a few years gained.

Dopaminergic neurons are critical modulators for essential brain functions such as learning and memory, reward and addiction, motor control, and metabolism. My recent work identified a novel function of dopaminergic neurons in regulating aging and longevity in flies. I demonstrated that overexpressing the putative scaffolding protein Mask in small subsets of dopaminergic neurons significantly extends the lifespan in flies. Interestingly, the prolonged lifespan of the Mask-overexpressing flies is accompanied by sustained reproductive activities, contradicting the long-acknowledged inverse relation between reproduction and longevity.

This prevalent negative correlation between reproduction and longevity has been explained by the disposability theory that posits a competing allocation of energy between reproduction and somatic maintenance. However, my work, together with a few other findings in flies, suggested that extension of both lifespan and reproduction can be induced simultaneously by a variety of specific genetic manipulations. Moreover, such a co-extension also occurs in nature - the reproductive females of eusocial insects acquire physiological transformations that enable the expansion of both their reproduction capacity and lifespan.

It seems that a common mechanism may exist to actively induce adaptations to cope with the reproductive demands of the animals, which also at the same time intervenes the aging process and extends the lifespan. Inspired by this notion, I propose a reproduction-centered theory that explains the seemingly contradictory relationships of reproduction and longevity. The success of reproduction is essential for the survival of the species. From such a reproduction-centered perspective, the maintenance of the somatic tissues is not just critical for the survival of individuals but is, more importantly, essential for the fulfillment of reproduction. Therefore, I postulate that somatic tissues possess the ability to adapt to, instead of competing with, the animal's reproduction states and that such adaptations can consequentially impact aging and longevity.

Link: https://doi.org/10.18632/aging.204000

There is some debate over whether age-related hearing loss is a matter of loss of hair cells in the inner ear, or a loss of the connections between those cells and the brain. Since various groups are working towards hair cell regeneration, including the one noted here, this debate should be resolved not too many years from now. The easiest way to answer questions of this nature, meaning which form of biological damage is the important one in a given age-related condition, is to fix that damage and see what happens.

The biotechnology company Frequency Therapeutics is seeking to reverse hearing loss - not with hearing aids or implants, but with a new kind of regenerative therapy. The company uses small molecules to program progenitor cells, a descendant of stem cells in the inner ear, to create the tiny hair cells that allow us to hear. Hair cells die off when exposed to loud noises or drugs including certain chemotherapies and antibiotics. Frequency's drug candidate is designed to be injected into the ear to regenerate these cells within the cochlea. In clinical trials, the company has already improved people's hearing as measured by tests of speech perception - the ability to understand speech and recognize words.

The company has dosed more than 200 patients to date and has seen clinically meaningful improvements in speech perception in three separate clinical studies. Another study failed to show improvements in hearing compared to the placebo group, but the company attributes that result to flaws in the design of the trial. Now Frequency is recruiting for a 124-person trial from which preliminary results should be available early next year.

Progenitor cells reside in the inner ear and generate hair cells when humans are in utero, but they become dormant before birth and never again turn into more specialized cells such as the hair cells of the cochlea. Humans are born with about 15,000 hair cells in each cochlea. Such cells die over time and never regenerate. In 2012, the research team was able to use small molecules to turn progenitor cells into thousands of hair cells in the lab. The researchers believe their approach offers advantages over gene therapies, which may rely on extracting a patient's cells, programming them in a lab, and then delivering them to the right area.

Link: https://news.mit.edu/2022/frequency-therapeutics-hearing-regeneration-0329

Partial reprogramming involves exposing cells to the Yamanaka factors capable of turning somatic cells into induced pluripotent stem cells, but not for so long as to result in that transformation. The initial stage of reprogramming, prior to transformation into stem cells, in which epigenetic marks are reset to a youthful configuration, is the desirable outcome. This results in rejuvenation of cell function, as protein production and the operation of cellular processes return to that of youth. This cannot repair DNA damage, and will probably help little with problems relating to persistent metabolic waste in long-lived cells, but the evidence from animal studies suggests that partial reprogramming can be beneficial enough to form the basis for a true rejuvenation therapy.

Partial reprogramming is a relatively new line of research and development, through very well funded of late. Numerous biotech companies are working towards the production of therapies based upon partial reprogramming techniques. These are first generation efforts, however, and the research community will inevitably improve upon the protocols of partial reprogramming, even as the first commercial efforts move towards the clinic. Today's research materials are an example of the sort of work taking place in this part of the field: attempts to optimize partial reprogramming in cell culture, alongside better measurements of the degree to which benefits to cell function are produced.

A jump through time - new technique rewinds the age of skin cells by 30 years

The full process of stem cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called 'maturation phase transient reprogramming', exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.

Researchers looked at multiple measures of cellular age. The first is the epigenetic clock, where chemical tags present throughout the genome indicate age. The second is the transcriptome, all the gene readouts produced by the cell. By these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets. "Our results represent a big step forward in our understanding of cell reprogramming. We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of ageing indicators in genes associated with diseases is particularly promising for the future of this work."

Multi-omic rejuvenation of human cells by maturation phase transient reprogramming

Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse age-associated changes. However, during iPSC reprogramming, somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first 'maturation phase transient reprogramming' (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction.

Using dermal fibroblasts from middle age donors, we found that cells temporarily lose and then reacquire their fibroblast identity during MPTR, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent.

The magnitude of rejuvenation instigated by MTPR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that more extensive reprogramming does not necessarily result in greater rejuvenation but instead that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.

Researchers here discuss a model of Alzheimer's disease that is centered around consequences of the age-related disruption of the blood-brain barrier. This barrier of specialized cells lines blood vessels in the central nervous system, and acts to control the passage of cells and molecules to and from the brain. Unfortunately, it becomes leaky with age, failing just like every other system and structure in the body. The researchers propose an interesting hypothesis, but it stands as one of many new ways to look at Alzheimer's disease. A great deal of theorizing has been provoked by the ongoing failure to make progress in the development of therapies to meaningfully slow or reverse the progression of this form of neurodegeneration. It remains to be seen as to whether any of it will lead to better roads forward.

We propose a new hypothesis for Alzheimer's disease (AD) - the lipid invasion model. It argues that AD results from external influx of free fatty acids (FFAs) and lipid-rich lipoproteins into the brain, following disruption of the blood-brain barrier (BBB). The lipid invasion model explains how the influx of albumin-bound FFAs via a disrupted BBB induces bioenergetic changes and oxidative stress, stimulates microglia-driven neuroinflammation, and causes anterograde amnesia. It also explains how the influx of external lipoproteins, which are much larger and more lipid-rich, especially more cholesterol-rich, than those normally present in the brain, causes endosomal-lysosomal abnormalities and overproduction of the peptide amyloid-β (Aβ). This leads to the formation of amyloid plaques and neurofibrillary tangles, the most well-known hallmarks of AD.

The lipid invasion model argues that a key role of the BBB is protecting the brain from external lipid access. It shows how the BBB can be damaged by excess Aβ, as well as by most other known risk factors for AD, including aging, apolipoprotein E4 (APOE4), and lifestyle factors such as hypertension, smoking, obesity, diabetes, chronic sleep deprivation, stress, and head injury. The lipid invasion model gives a new rationale for what we already know about AD, explaining its many associated risk factors and neuropathologies, including some that are less well-accounted for in other explanations of AD. It offers new insights and suggests new ways to prevent, detect, and treat this destructive disease and potentially other neurodegenerative diseases.

Link: https://doi.org/10.3233/ADR-210299

Given the onset of a particular type of cancer, why does that cancer become a much worse prospect for only some individuals? Why are some people more prone to metastasis, for example? A perhaps underappreciated factor is the interaction of infectious agents with the tumor microenvironment, as researchers discuss here. Exposure to pathogens, and particularly persistent pathogens, may be a good explanation for many areas of medicine in which only some people bearing all of the traditional risk factors go on to develop the worst outcomes.

Microbes play a critical role in affecting cancer susceptibility and tumor progression, particularly in colorectal cancers. However, emerging evidence suggests that they are also integral components of the tumor tissue itself in in a broad range of cancer types, such as pancreatic cancer, lung cancer, and breast cancer. Microbial features are linked to cancer risk, prognosis, and treatment responses, yet the biological functions of tumor-resident microbes in tumor progression remain unclear.

Whether these microbes are passengers or drivers of tumor progression has been an intriguing question. Researchers used a mouse model of breast cancer with significant amounts of bacteria inside cells, similar to human breast cancer. They found that the microbes can travel through the circulatory system with the cancer cells and play critical roles in tumor metastasis. Specifically, these passenger bacteria are able to modulate the cellular actin network and promoted cell survival against mechanical stress in circulation.

"We were surprised initially at the fact that such a low abundance of bacteria could exert such a crucial role in cancer metastasis. What is even more astonishing is that only one shot of bacteria injection into the breast tumor can cause a tumor that originally rarely metastasizes to start to metastasize. Intracellular microbiota could be a potential target for preventing metastasis in broad cancer types at an early stage, which is much better than to have to treat it later on."

Link: https://www.eurekalert.org/news-releases/948302

Mitochondrial uncoupling is a mechanism by which mammals maintain body temperature. It diverts the activity of the hundreds of mitochondria present in every cell from production of the chemical energy store molecule adenosine triphosphate (ATP), used to power cellular processes, to the production of heat. Additional mitochondrial uncoupling, above and beyond that which occurs naturally, produces beneficial effects on long term health, as is true of a range of manipulations that influence mitochondrial function. In this case, however, it doesn't appear to slow aging, even while resulting in desirable outcomes such as a reduction in visceral fat tissue.

Mild additional mitochondrial uncoupling is a good thing. Excessive mitochondrial uncoupling can produce severe side-effects and death, however, and that makes it a tricky process to produce drugs targeting this mechanism. One of the world's more dangerous and interesting drugs is a mitochondrial uncoupler, 2,4-dinitrophenol (DNP). In addition to being an explosive compound, it stays in the body long enough to make it all too easy to slip from a safe dose to potentially fatal dose. It is thus no longer used, after a period of interest as a weight loss treatment many decades ago.

The effects of mitochondrial uncoupling on long term health are interesting enough, in this era of widespread obesity, for the research community to have worked towards safe mitochondrial uncoupling compounds. One of these, BAM15, is the subject of today's research materials. You may recall that this line of work was discussed here a few years ago. There is progress towards a potential path to the clinic, but only slowly, as is usually the case.

Chemical Compound Promotes Healthy Aging

Researchers have provided the first evidence that BAM15, a mitochondrial uncoupler, prevents sarcopenic obesity, or age-related muscle loss accompanied by an increase in fat tissue. The weakness and frailty common to sarcopenic obesity are offset in older mice - the equivalent of aged 60-65 in human years - given BAM15. The mice, all of whom had obesity, were fed high-fat diets. Despite that, the mice given BAM15 lost weight and got stronger and more active. "In this study, the aged mice increased their muscle mass by an average of 8 percent, their strength by 40 percent, while they lost more than 20 percent of their fat."

BAM15 improves many of the key determinants of health and aging, including: (a) removing damaged mitochondria, the power plants of the cell; (b) making more healthy mitochondria, and; (c) reducing "inflammaging," or age-related inflammation, linked to muscle loss.

Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control

Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.

BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g) which was attributable to increased energy expenditure. BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g), and locomotor activity. Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation, enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control, increased mitochondrial activity, restricted endoplasmic reticulum (ER) misfolding, while limiting ER stress, apoptotic signalling, and muscle protein degradation.

There is no shortage of theorizing in the Alzheimer's disease community. The lengthy failure of therapies targeting amyloid-β, first the failure to clear amyloid-β meaningfully, and then the failure to produce benefits in patients after clearance was achieved, has led to a great deal of frustration and the search for new views of the condition that might lead to different therapeutic strategies. Many of these viewpoints should probably be taken with a grain of salt (e.g. that modern painkillers play an important role), while others are quite compelling (e.g. persistent viral infection, or the burden of cellular senescence in supporting cells in the brain). Today's example is an interesting reframing of what is known of the role of amyloid-β in the innate immune system, and how that might apply to Alzheimer's disease.

As new potentially explanatory biochemical mechanisms for Alzheimer's disease (AD) emerge, they are often regarded as mutually exclusive and in competition - a situation resulting in pronouncements that the amyloid hypothesis, plagued by numerous clinical trial failures, is dead and needs to be replaced. However, a variety of data compellingly link amyloid beta (Aβ) to the pathogenesis of AD. Accordingly, rather than categorically rejecting the role of Aβ, the need for a new widely encompassing conceptualization of AD that unifies seemingly divergent theories into a single harmonized explanation emerges as an effective strategy. Incorporating protein misfolding mechanisms into a broader-based immunopathic model of AD could attain such a goal - a goal which can be achieved by repositioning Aβ as an immunopeptide.

In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self-perpetuating autoimmune cycle. AD thus emerges as a brain-centric autoimmune disorder of innate immunity.

Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in the human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex pathogenesis.

Link: https://doi.org/10.1002/trc2.12283

Researchers here note that mitochondrially targeted tamoxifen, developed as a cancer therapeutic, is sufficiently senolytic to treat conditions in which senescent cells play a significant role. They have chosen to target type 2 diabetes, a case of following the money given the present epidemic of obesity. It is actually quite surprising that few of the groups developing novel senolytic drugs have set their sights on diabetes, given the solid evidence of the past few years for the pathology of both type 1 diabetes and type 2 diabetes to be mediated in large part by cellular senescence.

Senescent cells play an important role in the induction of type 2 diabetes mellitus (T2DM) pathogenesis. Considering that metabolic and signaling changes associated with T2DM can promote senescence, senescent cells are components of the "pathogenic loop" in diabetes. In obese and diabetic mice, visceral adipose tissue (VAT) is the most prominent compartment of senescent cells accumulation. VAT, therefore, presents the nexus of mechanisms involved in longevity and age-related metabolic dysfunctions. A close relationship between visceral fat content and the risk of T2DM and cardiovascular complications has also been demonstrated in humans. Components of the senescence-associated secretory phenotype (SASP) secreted by adipose-derived senescent cells confer insulin resistance to metabolic tissues and attract immune cells that can exacerbate the effects of insulin resistance. Moreover, there is a close relationship between senescence and fat accumulation in hepatocytes followed by the development of steatosis in diabetic mice.

Senolytic agents may improve glucose control and obesity- and diabetes-related pathologies, supporting the idea that targeting senescent cells may be a promising strategy for T2DM management. Mitochondrial function is an important determinant of the aging process, and we have recently reported that targeting mitochondria in senescent cells presents a plausible way to eliminate such cells in the context of pathological senescence as well as senescence-associated diseases. Using mitochondrially targeted tamoxifen (MitoTam), our proprietary agent with anticancer activity, we have achieved specific elimination of senescent cells.

Treatment with MitoTam effectively reduces oxidative phosphorylation (OXPHOS) and mitochondrial membrane potential in senescent cells, and severely affects mitochondrial morphology based on a low level of the ADP/ATP translocation channel ANT2 (adenine nucleotide translocase 2). These cells cannot, therefore, pump ATP inside mitochondria in order to maintain mitochondrial potential by cleavage of ATP by ATPase, resulting in the collapse of mitochondrial integrity and function18. Based on these results, we reasoned that MitoTam may present a non-cannonical therapeutic modality to treat senescence-associated pathologies, such as T2DM.

Here we show that MitoTam considerably improves glucose control, decreases body weight, and reduces diabetic markers as well as diabetic comorbidities in mice with diet-induced obesity and prediabetes. These improvements are associated not only with a reduction of food intake and a drop in the number of senescent cells in the organism but also with rejuvenation of the adipose tissue, suggesting the role of MitoTam in T2DM treatment and prevention of chronic diabetic complications.

Link: https://doi.org/10.1038/s41467-022-29486-z

A growing burden of senescent cells in tissues throughout the body is an important contributing cause of degenerative aging. These cells secrete pro-growth, pro-inflammatory signals that, when maintained for the long term, are highly disruptive of cell and tissue function. Cellular senescence is an important contributing cause in many age-related conditions. Senescent cells are created constantly throughout life, and the immune system is responsible for removing those that fail to destroy themselves. Unfortunately, it becomes worse at this task with age.

Natural killer cells are one of the immune cell populations involved in senescent cell clearance, and researchers are interested in ways to enhance this ability. One possibility is to increase the number of natural killer cells present in the body. In today's open access paper, rsearchers here show that providing additional natural killer cells in the form of a cell therapy can reduce the burden of senescent cells in mice. They additionally propose ways to enhance the ability of transplanted cells to clear lingering senescent cells.

Combining adoptive NK cell infusion with a dopamine-releasing peptide reduces senescent cells in aged mice

Senescent cells (SNCs) can be recognized and removed by the immune system. Previous studies have shown that SNCs activate natural killer (NK) cells by up regulating the major histocompability class I chain-related protein A and B activating ligand. However, with increasing age, the efficiency of the immune system decreases, which can lead to the immune escape of SNCs. Methods to overcome immune escape caused by decreased immune function have been explored in cancer therapy. Recent progress has been made in adoptively transferring NK cells to eliminate tumours, which has shown some efficacy; thus, it was reasonable to assume that the adoptive infusion of NK cells might produce cytotoxicity in SNCs.

The nervous and immune systems are the two most important adaptive systems of the body. Several studies have shown that dopamine (DA) as an immune regulator is a key to the neuroimmune communication. DA performs its biological functions by interaction with and activation of dopamine receptors (DR), which are divided into 2 subgroups, D1-like (D1 and D5), and D2-like (D2, D3, and D4). In terms of their different functions, the engagement of D1-like DR stimulates cAMP production, while the engagement of D2-like DR inhibits cAMP production. Previous studies have shown that D1-like DR stimulation enhances the cytotoxicity of NK cells both in vitro and in vivo. However, DA levels drop as human age increase. Thus, we hypothesized that dopaminergic drugs could enhance cytotoxicity of the adoptive infusion of NK cells.

Here, we propose the use of the nonapeptide Acein, which interacted with angiotensin converting enzyme (ACE I) to induce DA secretion, in combination with systemic NK cell therapy to eliminate SNCs. In vitro results showed that NK cells removed SNCs, independently of senescence inducers and cell types. In an aging mouse model, NK cell therapy in combination with Acein significantly reduced the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells in multiple tissues, decreased the expression of senescence-associated genes in major organs, and alleviated senescence-associated secretory phenotypes (SASPs). The results of this study provide insights into possible restoration of the immune surveillance of chronic SNCs using NK cell therapy in combination with Acein.

Mitochondria are essential cell components that become dysfunctional with age, a cause of a significant fraction of age-related degeneration. These organelles are descended from ancient symbiotic bacteria, and the herd of mitochondria in a cell is dynamic, fusing together, splitting apart, and passing around component parts. As mitochondria become worn and damaged, they are removed by the quality control process of mitophagy. This all works well in youth.

In the context of aging, a fair amount of evidence points to impaired mitochondrial fission as an important contributing cause of impaired mitophagy, which in turn leads to impaired mitochondrial function as damaged mitochondria accumulate, which in turn causes all sorts of issues. The issue in question here is the reduced generation of new blood vessels with age, an impairment that may be very significant, as it contributes to the decline of capillary networks throughout the body and reduced blood supply to energy-hungry organs such as muscles and the brain.

The protein Drp1 is best known to enable an orderly splitting, or fission, of mitochondria so that one becomes two and/or mitophagy, which is trimming off dysfunctional parts of existing mitochondria and helping eliminate mitochondria that are beyond repair. Researchers now have early evidence that when oxygen levels are low in common problems like heart disease and peripheral artery disease in the legs, Drp1 gets modified and a new job. It again promotes splitting, or fission, of the powerhouses but in this case, the magic is in generating a powerful signal, via creation of reactive oxygen species (ROS), that makes glycolysis happen. Ready energy like from glycolysis is needed for the cell proliferation, migration, and movement of angiogenesis, and the endothelial cells that line existing blood vessels take the lead in making new ones.

Hypoxia, like the heart muscle crying out for more oxygen, is the natural cue for angiogenesis. Vascular endothelial growth factor (VEGF), which does just what its name implies, outside the endothelial cell is naturally stimulated by hypoxia, then in turn activates NADPH oxidase, a family of enzymes that generate ROS - in this case the kind that enables cell signaling. ROS generated by the mitochondria in turn activates AMPK, an enzyme key to regulating energy levels in cells and known to use glucose to quickly generate sufficient energy to support important biological work like making new blood vessels.

When ROS from the mitochondria is blocked, angiogenesis produced by endothelial cells also is impaired. And it appears to be a two-way street because VEGF's ability to enable angiogenesis also is impaired, and mitochondrial ROS can activate NADPH oxidase ROS and vice versa. Together the result is sustained signaling. If you block mitochondrial ROS, the chain reaction is blocked.

Link: https://jagwire.augusta.edu/powerhouse-pruning-protein-may-also-aid-new-blood-vessel-growth-in-vascular-disease/

Researchers here show that, in primates, oocyte cells are more protected from mutations to mitochondrial DNA in later life. This suggests that one or more mechanisms are operating to produce this outcome. Given that mitochondrial DNA mutations are implicated in age-related loss of mitochondrial function and other aspects of aging, the existence of protective mechanisms is potentially interesting. It is not as interesting as the ability to repair or replace damaged mitochondrial DNA, of course. Mechanisms that can only produce sizable differences by operating over long periods of time are a poor foundation upon which to build rejuvenation therapies.

New mutations occur at increasing rates in the mitochondrial genomes of developing egg cells in aging rhesus monkeys, but the increases appear to plateau at a certain age and are not as large as those seen in non-reproductive cells, like muscle and liver. A new study using an accurate DNA sequencing methodology suggests that there may be a protective mechanism that keeps the mutation rate in reproductive cells relatively lower compared to other tissues in primates, a fact that could be related to the primate - and therefore human - propensity to reproduce at later ages.

Mitochondria are cellular organelles - often called the powerhouse of the cell because of their role in energy production - that have a genome of their own separate from the cell's nuclear genome. Researchers sequenced the mitochondrial genome from muscle cells, liver cells, and oocytes - precursor cells in the ovary that can become egg cells - in rhesus macaques that ranged in age from one to 23 years. This age range covers almost the entire reproductive lifespan of the monkeys. Tissues for the study were collected opportunistically over the course of several years from primate research centers when animals died of natural causes or were sacrificed because of diseases not related to reproduction. Oocytes, and not sperm cells, were used because mitochondria are inherited exclusively through the maternal line.

Overall, the researchers saw an increase in the mutation frequency in all of the tested tissues as the macaques aged. Liver cells experienced the most dramatic change with a 3.5-fold increase in mutation frequency over approximately 20 years. The mutation frequency in muscle increased 2.8-fold over the same time span. The mutation frequency in oocytes increased by 2.5-fold up to age nine, at which point it remained steady. Our results suggest that primate oocytes might have a mechanism to protect or repair their mitochondrial DNA, an adaptation that helps to allow later reproduction. The precise mechanism leading to the plateau in mutation frequency in oocytes remains enigmatic, but it might act at the level of elimination of defective mitochondria or oocytes."

Link: https://science.psu.edu/news/Makova4-2022

Forms of autophagy function to remove unwanted, excess, or damaged structures and other molecules in the cell. These materials are delivered to a lysosome, a membrane packed with enzymes capable of dismantling near every macromolecule a cell will encounter, producing raw materials for reuse. Autophagy is quite clearly connected to tissue function and aging in a number of ways. It appears to decline in quality with age, leading to downstream problems in cell and tissue function as worn and damaged component parts accumulate. Upregulation of autophagy for long periods of time is a feature of numerous interventions, such as calorie restriction and calorie restriction mimetics, that result in slowed aging.

In today's research materials, the team involved in developing autophagy-upregulating small molecule therapies at Life Biosciences discuss evidence for chaperone-mediated autophagy to be relevant in atherosclerosis. In atherosclerosis, fatty deposits build up in blood vessels as a result of macrophages becoming less capable of returning excess cholesterol to the blood stream. The chronic inflammation and oxidative stress of age disrupts the ability of macrophages sufficiently to allow atherosclerotic plaques to form in the first place, but once formed the plaque is a hostile environment that overwhelms macrophages with excess cholesterol.

Anything that improves macrophage resilience can help. It is actually not that hard to significantly slow the growth of atherosclerotic plaque in mice, and many methods work well. Small differences sustained over time add up. Reversal of atherosclerosis is a much harder problem, and the work involving increased autophagy noted here is not a demonstration of reversal, but rather just another demonstration of slowed atherosclerosis. In that sense, it is not that exciting; it is on a par with what can be done with drugs like statins that lower blood cholesterol. Lower blood cholesterol over a lifetime can halve the risk of dying due to atherosclerosis in humans, but statins as a treatment applied in old age are nowhere near that good at reducing cardiovascular mortality.

Researchers Find New Strategy for Preventing Clogged Arteries

Chaperone-mediated autophagy (CMA) keeps cells functioning normally by selectively degrading the many proteins that cells contain. In CMA, specialized chaperone proteins bind to proteins in the cytoplasm and guide them to enzyme-filled cellular structures called lysosomes to be digested and recycled. Disrupted CMA allows damaged proteins to accumulate to toxic levels, contributing to aging and - when the toxic buildup occurs in nerve cells - to neurodegenerative diseases including Parkinson's, Alzheimer's, and Huntington's disease.

To investigate CMA's role in atherosclerosis, researchers promoted atherosclerosis in mice by feeding them a fatty Western diet for 12 weeks and monitoring CMA activity in plaque-affected aortas of the animals. CMA activity initially increased in response to the dietary challenge; after 12 weeks, however, plaque buildup was significant, and virtually no CMA activity could be detected in the two types of cells - macrophages and arterial smooth muscle cells - that are known to malfunction in atherosclerosis, leading to the buildup of plaque within arteries. Feeding the high-fat diet to mice totally lacking in CMA activity produced even stronger evidence of CMA's importance: plaques nearly 40% larger than those in control animals that were also on the high-fat diet.

The researchers genetically "upregulated" CMA in mice that were fed a pro-atherosclerotic, high-fat Western diet and later compared them with control mice fed the same diet for 12 weeks. The CMA-boosted mice had greatly improved blood lipid profiles, with markedly reduced levels of cholesterol compared with the control mice. Plaque lesions that formed in the genetically altered mice were significantly smaller and milder in severity compared with plaques in control mice.

Protective role of chaperone-mediated autophagy against atherosclerosis

Cardiovascular diseases remain the leading cause of death worldwide, with atherosclerosis being the most common source of clinical events. Metabolic changes with aging associate with concurrent increased risk of both type 2 diabetes and cardiovascular disease, with the former further raising the risk of the latter. The activity of a selective type of autophagy, chaperone-mediated autophagy (CMA), decreases with age or upon dietary excesses. Here we study whether reduced CMA activity increases risk of atherosclerosis in mouse models. We have identified that CMA is up-regulated early in response to pro-atherogenic challenges and demonstrate that reduced systemic CMA aggravates vascular pathology in these conditions. We also provide proof-of-concept support that CMA up-regulation is an effective intervention to reduce atherosclerosis severity and progression.

Senolytic drugs capable of clearing senescent cells from the bodies of older people will be a very important part of the medicine of tomorrow. A burden of senescent cells contributes significantly to aging, and removing them produces quite rapid and profound rejuvenation in animal models. If taking the small molecule drug approach, a diversity of senolytics will likely be needed in order to clear most senescent cells from most tissues, due to differences in drug biodistribution and biochemistry of senescence between tissue types. The search for new senolytic drug targets and drug compounds has been underway in earnest for a few years, and researchers are starting to become more rigorous and systematic, as demonstrated here.

Selectively ablating senescent cells ("senolysis") is an evolving therapeutic approach for age-related diseases. Current senolytics are limited to local administration by potency and side effects. While genetic screens could identify senolytics, current screens are underpowered for identifying genes that regulate cell death due to limitations in screen methodology.

Here, we establish Death-seq, a positive selection CRISPR screen optimized to identify enhancers and mechanisms of cell death. Our screens identified synergistic enhancers of cell death induced by the known senolytic ABT-263, a BH3 mimetic. SMAC mimetics, enhancers of cell death in our screens, synergize with ABT-199, another BH3 mimetic that is not senolytic alone, clearing senescent cells in models of age-related disease while sparing human platelets, avoiding the thrombocytopenia associated with ABT-263.

In summary, Death-seq enables the systematic screening of cell death pathways to uncover molecular mechanisms of regulated cell death subroutines and identify drug targets for diverse pathological states such as senescence, cancer, and neurodegeneration.

Link: https://doi.org/10.1101/2022.04.01.486768

The non-profit SENS Research Foundation is expanding their research center in the Bay Area. A number of interesting projects relevant to human rejuvenation are underway at their facility, such as work on allotopic expression of mitochondrial genes. This follows a sizable increase in funding last year, arriving from the cryptocurrency community. One of the more interesting and perhaps less visible consequences of the use of blockchains to create cryptocurrencies is a concentration of wealth in the hands of comparatively young, comparatively visionary people who are willing to try to change the world, such as by, for example, funding high risk, high reward projects in medical research and development.

We are thrilled to announce the expansion of the SENS Research Foundation's Research Center to over 11,000 square feet with the addition of new lab and office space. This is more than doubling our current facility in Mountain View, California that is home to the foundation' global operations.

Thank you to all the donors who made this expansion possible. We are grateful beyond words for your ongoing support, as it has enabled us to rapidly expand not just our lab space, but our internal research programs, as well as the equipment and other resources needed to accelerate the defeat of age-related disease. We will host a Grand Re-Opening early this summer to which everyone will be invited - watch your inbox and stay tuned for details.

Link: https://www.sens.org/announcing-the-expansion-of-our-research-center/

Early atherosclerosis, meaning the stage at which there are only smaller, still-harmless fatty deposits in artery walls, is present in a sizable fraction of people in their 40s. This can be evaluated with imaging technologies, but suitable imaging approaches are comparatively expensive. Given a reliable, cheaper way to detect this early progression of the condition, adjustments in lifestyle and application of therapies might significantly postpone later mortality. It is always easier to start early in order to slow progression of age-related disease than it is to attempt to fix matters later, once atherosclerotic plaque is more developed and life-threatening.

Established plaque cannot be meaningfully reversed using presently available therapies. In particular, lowering LDL cholesterol in the bloodstream, via statins and the like, has little effect on plaque size. Given approaches under development, it will be possible to reverse plaque and aim for a cure for atherosclerosis in the future, however. Given the development of therapies capable of this goal, only realized in animal studies to date, then a marker of early atherosclerosis could lead to early reversal, periodic clearance of preclinical plaque in order to prevent atherosclerosis from ever developing.

Unbiased plasma proteomics discovery of biomarkers for improved detection of subclinical atherosclerosis

Imaging of subclinical atherosclerosis improves cardiovascular risk prediction on top of traditional risk factors. However, cardiovascular imaging is not universally available. This work aims to identify circulating proteins that could predict subclinical atherosclerosis. Hypothesis-free proteomics was used to analyze plasma from 444 subjects from PESA cohort study (222 with extensive atherosclerosis on imaging, and 222 matched controls) at two timepoints (three years apart) for discovery, and from 350 subjects from AWHS cohort study (175 subjects with extensive atherosclerosis on imaging and 175 matched controls) for external validation. A selected three-protein panel was further validated by immunoturbidimetry in the AWHS population and in 2999 subjects from ILERVAS cohort study.

PIGR, IGHA2, APOA, HPT, and HEP2 were associated with subclinical atherosclerosis independently from traditional risk factors at both timepoints in the discovery and validation cohorts. Multivariate analysis rendered a potential three-protein biomarker panel, including IGHA2, APOA, and HPT. Immunoturbidimetry confirmed the independent associations of these three proteins with subclinical atherosclerosis in AWHS and ILERVAS. A machine-learning model with these three proteins was able to predict subclinical atherosclerosis in ILERVAS, and also in the subpopulation of individuals with low cardiovascular risk.

In conclusion, plasma levels of IGHA2, APOA and HPT are associated with subclinical atherosclerosis independently of traditional risk factors and offers potential to predict this disease. The panel could improve primary prevention strategies in areas where imaging is not available.

Forms of stem cell therapy, such as those using mesenchymal stem cells, are now fairly common. They are unreliable when it comes to spurring regeneration, the original goal, but they do well when it comes to reducing chronic inflammation in the context of age-related conditions. Working with cells is, however, comparatively costly and comes with a number of logistical issues regarding production, quality, storage, transport, and so forth.

Since this type of cell therapy likely achieves the majority of its beneficial effects via the signaling produced by transplanted cells in the short period of time before they die, academia and industry is ever more focused on reproducing that signaling without the need for cells. Exosomes are membrane-bound packages of signal molecules secreted by cells, and one of the primary means by which stem cells affect the behavior of surrounding cells. Once harvested from stem cells in culture, exosomes are much easier to store and use in therapy than is the case for the cells themselves, while still appearing to deliver similar benefits in the context of first generation stem cell therapies.

Exosomes harvested from mesenchymal stem cells (MSCs-Exo), as a treatment for diseases, has better safety and convenience compared with stem cell therapy, and will certainly play a huge role in the future clinical treatment of diseases. Exosomes as the carrier of therapy can be applied to a variety of diseases, to achieve the effect that conventional therapy cannot achieve. As biologically active nano-vesicles, MSCs-Exo have shown many advantages in disease treatment, such as cardiovascular disease, neurodegenerative disease, tumors, and regenerative medicine.

Currently, an accumulating amount of evidence has been showing that MSCs-Exo has disease treating potential and can successfully apply for the therapy of several kinds of disease. A few clinical trials are currently on-going but there are still challenges to overcome for further clinical translation such as the scale-up of the production, the lack of standardization for isolation and characterization methods and the low encapsulation efficiency. In contrast with MSCs, evidence suggests that MSCs-Exo promotes angiogenesis, restrains inflammatory effects, decreases immunogenicity, and reduces tumor production.

As a therapeutic tool, compared with standard delivery methods, MSCs-Exo holds great therapeutic promise, but still faces many challenges. Due to the size and complexity of MSCs-Exo, there are challenges in clinical practice, such as large-scale pharmaceutical production and production costs. Previously, scientists used ultracentrifugation to purify exosomes, which was a labor-intensive and time-consuming process that could not be used for large-scale production. The focus of future research is to find new solutions in future research and develop a simple purification method with very low cost and safety.

Link: https://doi.org/10.3390/pharmaceutics14030618

Proteases are an important category of molecular machinery in the cell, one of several responsible for breaking down proteins and other molecules into component parts that can be recycled. Proteases operate as a part of the cellular maintenance processes that remove excess or damaged and potentially damaging structures and proteins. The quality of this cellular maintenance influences cell and tissue function, and improved maintenance is a feature of many interventions, genetic and otherwise, that modestly slow aging in short-lived laboratory species. Looking at all proteases in the context of aging is a little broad for one paper, but the authors here outline the high level view and some specific examples.

Protein quality control ensures the degradation of damaged and misfolded proteins. Derangement of proteostasis is a primary cause of aging and age-associated diseases. The ubiquitin-proteasome and autophagy-lysosome play key roles in proteostasis but, in addition to these systems, the human genome encodes for ~600 proteases, also known as peptidases. Here, we examine the role of proteases in aging and age-related neurodegeneration. Proteases are present across cell compartments, including the extracellular space, and their substrates encompass cellular constituents, proteins with signaling functions, and misfolded proteins.

Proteolytic processing by proteases can lead to changes in the activity and localization of substrates or to their degradation. Proteases cooperate with the autophagy-lysosome and ubiquitin-proteasome systems but also have independent proteolytic roles that impact all hallmarks of cellular aging. Specifically, proteases regulate mitochondrial function, DNA damage repair, cellular senescence, nutrient sensing, stem cell properties and regeneration, protein quality control and stress responses, and intercellular signaling. The capacity of proteases to regulate cellular functions translates into important roles in preserving tissue homeostasis during aging.

Consequently, proteases influence the onset and progression of age-related pathologies and are important determinants of health span. Specifically, we examine how certain proteases promote the progression of Alzheimer's, Huntington's, and/or Parkinson's disease whereas other proteases protect from neurodegeneration. Mechanistically, cleavage by proteases can lead to the degradation of a pathogenic protein and hence impede disease pathogenesis. Alternatively, proteases can generate substrate byproducts with increased toxicity, which promote disease progression. Altogether, these studies indicate the importance of proteases in aging and age-related neurodegeneration.

Link: https://doi.org/10.1111/acel.13603

The authors of today's open access paper argue for much greater effort to be directed towards the repurposing of existing drugs with the goal of slowing aging. I have mixed feelings about the prevalence of drug repurposing in the pharmaceutical industry. The FDA makes it so very expensive to introduce any new drug that industry of course responds to the incentives and spends a great deal of time digging through the existing library of approved drugs in search of those that can be used in different circumstances. It is a great deal easier to take a drug with established safety data and seek approval for a new use than it is to carry out the same regulatory process for a new drug.

On the one hand, this search of existing drug databases can turn up items like the dasatinib and quercetin combination, a senolytic therapy that is producing impressive displays of rejuvenation in old mice. This is an unusual outcome, and didn't exactly arise from the usual drug repurposing channels, but if it had arisen that way, then it might in and of itself justify much of the effort across the industry.

Looking at the broader picture, however, this part of the pharmaceutical industry appears to specialize in pushing entirely marginal therapies into the FDA process. The benefit of known safety data is balanced against (usually) poor performance in treating the target condition in question. If there are presently only poor options for the treatment of a given condition, then a still poor but incrementally better option can achieve regulatory approval. The treatment of aging is currently in this position, and hence the paper here puts forward a list of largely unambitious items - plus dasatinib and quercetin. We live in interesting times.

Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization

Geroscience represents a novel paradigm whereby biological aging is recognized as the major modifiable driver of age-related diseases and other late-life conditions. Widespread clinical use of geroscience-guided interventions could transform the public health landscape because the ability to target biological aging as a risk factor could simultaneously delay the onset and progression of multiple conditions, thereby enhancing health, function, and independence in late-life. A corollary is that targeting this biology will affect human healthspan (the portion of lifespan free of major disease and disability) most profoundly, and with a better prognosis than the current model of addressing one disease at a time.

While aging is unequivocally the major risk factor for age-related diseases, regulatory bodies around the world, such as the FDA or EMA, do not yet recognize geroscience-guided clinical outcomes as a path to regulatory approval. This is in part because the processes for validating specific compounds or combinations of compounds for their ability to delay the onset and progression of multiple chronic diseases have not yet been delineated in humans. Without regulatory approval, insurers will not pay for such treatments, which disincentivizes pharmaceutical companies from developing geroscience-guided approaches, simply because there is no path for them to develop a viable business plan. Therefore, there is an urgent need to demonstrate, in a well-designed clinical trial, that a cluster of age-related diseases can be significantly delayed by repurposing existing or developing novel gerotherapeutics.

Targeting Aging with MEtformin (TAME) is such a study that has been under development for the last few years, and whose basic principles have been developed in consultation with the FDA. We believe that efforts to test and repurpose existing, safe gerotherapeutics should be extended beyond TAME, not only to increase the number of drugs potentially available to target aging in humans but also to mitigate the risks to the field, should any such trials fail to reach their desired outcome.

We sought to identify such FDA-approved drugs or classes of drugs that had at least one publication showing extension of lifespan in rodents and data in humans suggesting the highest chance of success if tested in a well-controlled TAME-like clinical trial. We developed a 12-point prioritization scale that assigns equal points for the preclinical and clinical evidence for each of these candidates. Points on the preclinical side were assigned for effects on the hallmarks of aging, improvement in healthspan and extension of lifespan in rodents as part of the NIA's Interventions Testing Program (ITP), a well-characterized, multicentered study to evaluate gerotherapeutics, as well as non-ITP rodent lifespan studies.

We were able to prioritize nine drug classes. SGLT2 inhibitors (SGLT2i), a relatively new drug class, was the only one to receive the maximum score, owing to not only its robust effects on improving rodent healthspan and lifespan (including ITP) but also strong evidence for the extension of healthspan and reduction of mortality in humans. Metformin was next on the list, and it received a submaximal score, due to negative findings for rodent lifespan extension in ITP. Acarbose, rapamycin/rapalogs, and methylene blue (MB) all had strong preclinical data and promising findings for human healthspan (the latter being the most robust for acarbose), but sparse clinical data for human mortality. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) were found to extend preclinical healthspan and lifespan (outside of ITP) and had robust effects on extending human healthspan, but the studies on human mortality, while abundant, were predominantly negative. The last three drugs on our list, senolytics Dasatinib + Quercetin (D + Q), aspirin, and N-acetyl cysteine (NAC), all had strong preclinical data, but their effects on human healthspan and mortality have not yet been assessed in clinical studies or appropriate doses/populations. Obviously, future studies may change the priority order for drugs that did not receive points due to the paucity of clinical data.

The immune system is a highly complex collection of many different types of specialized cells. As is usually the case in scientific research, some areas receive more attention than others, particularly in the context of aging, wherein funding is limited and there are fewer researchers focus on the topic. Of late natural killer cells have received more attention as a result of their role in clearance of senescent cells. Given that the research community has built the case that senescent cell accumulation is actually quite important in aging, finding out how and why the immune system fails to clear these cells in an aged tissue environment has become more of a pressing question.

Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer's and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease.

One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging ("inflammaging").

NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself.

Link: https://doi.org/10.3390/cells11061017

Naked mole rats are very long-lived in comparison to similarly sized rodents, and exhibit little functional decline until very late life. Along the way, they are also highly resistant to cancer. One aspect of their unusual physiology that likely contributes to both of these outcomes is a lower tendency towards age-related chronic inflammation. Naked mole rat senescent cells are nowhere near as inflammatory as the senescent cells of other mammals, for example, leaving naked mole rats largely unaffected by their accumulation with age. Here, researchers show that necroptosis, an inflammatory form of cell death that is both more common in age-damaged tissues and important in the pharmacological induction of cancer in animal models, operates poorly in naked mole rats.

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration.

NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs.

Link: https://doi.org/10.1038/s42003-022-03241-y

Few longevity-associated genes are demonstrated to work in both directions in animal studies, either enhancing or reducing life span depending on whether there is more or less of the protein produced. Klotho is one of the better studied examples. Here researchers note the evidence for C/EBPβ to be another such longevity gene, wherein more C/EBPβ leads to a shorter life span. Removing C/EBPβ completely is not a good idea, since it is essential for a variety of important aspects of our biology, such as the function of macrophage cells. Reducing it, however, extends life.

What can one do with this information? In the case of klotho, something approaching two decades of study has led to inroads toward an understanding of the mechanisms of importance, and a preclinical development program aimed at the use recombinant klotho protein as a therapy. There is clearly a long way to go yet. Like klotho, C/EBPβ influences a great many cellular mechanisms, and it will take a great deal of time and effort to even begin to distinguish what is important from what is a distraction. The wheels turn slowly when it comes to the effective manipulation of metabolism as a basis for treatments to slow aging.

C/EBPβ/AEP pathway dictates both Alzheimer's disease and longevity

C/EBPβ is a transcription factor that promotes Alzheimer's disease pathologies via activating asparagine endopeptidase (AEP) in response to amyloid-β and inflammatory cytokines.

To explore C/EBPβ's role in aged nerve cells, researchers generated a mouse model that selectively overexpresses C/EBPβ in the brain to mimic aged animals. Researchers found that the mice's life span was shortened in a gene dose-dependent manner. Usually, normal life expectancy for a mouse is around 24-28 months. However, the life span for a mouse carrying one copy of overexpressed C/EBPβ is around 12-18 months and 5-9 months for mice carrying two copies. By contrast, deleting one copy of the C/EBPβ gene increases the life span with the most long-lived mice living more than 30 months.

The C/EBPβ gene is elevated in human brains during aging. It peaks in individuals 60 to 84 years old and declines in those more than 85 years old. Long-lived individuals usually show less expression of AEP genes in nerve cells, whereas short-lived individuals show greater AEP gene expression.

In worms, neural excitation increases with age and inhibition of excitation increases longevity. The scientists found that high levels of C/EBPβ or AEP in nerve cells shorten the worm's life span, whereas such gene expression in muscles has no effect on longevity. Similar to mice, deletion of these genes in worms increases the life span. Remarkably, inhibition of AEP using a drug increases the life expectancy of worms.

Life span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism and longevity. The researchers found that C/EBPβ/AEP signaling was inversely correlated with insulin signaling in the human brain. With the lowest insulin signaling in humans in their seventies and eighties, C/EBPβ/AEP activity peaks. However, in humans with extended longevity, C/EBPβ/AEP activity declines, while insulin signaling climbs in the brain.

Neuronal C/EBPβ/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression

The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer's disease (AD). However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. Here, we show that C/EBPβ, an Aβ and inflammatory cytokine-activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose-dependent manner in neuronal C/EBPβ transgenic mice. C/EBPβ selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction.

Overexpression of CEBP-2 (ortholog of C/EBPβ) or LGMN-1 (orthology of AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces daf-2 mutant-elongated life span and diminishes daf-16-induced longevity. C/EBPβ and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPβ/AEP pathway.

Resistance training has been shown to reduce mortality in older adults. Muscle is a metabolically active tissue, and one of the mechanisms by which this mortality reduction is realized may be via lowered chronic inflammation. Old age is characterized by a rising level of inflammation, a reaction to molecular damage, the presence of senescent cells, and growing dysfunction of the immune system. As noted here, the balance of evidence from numerous studies shows a reduction in inflammatory signaling resulting from this form of exercise.

Exercise and weight control have been suggested as methods for mitigating the negative effects of chronic inflammation. Proper exercise has a dual effect in reducing chronic inflammation via weight reduction and lowering adipokines in cells. Resistance training (RT), a strength training exercise involving progressive overload in which the muscles exert force against an external load, could be a safe and effective method of improving chronic low-grade inflammation in older individuals.

A previous study reported that RT was associated with anti-inflammatory effects by decreasing serum levels of IL-6 and CRP, in addition to inducing changes in TNF-α gene expression in elderly women. However, another study suggested that RT was not related to TNF-α, IL-6, IL-10, and CRP improvement. As a result, an integrated and clear conclusion on the effects of RT in the elderly is currently unavailable. The purpose of this review was to critically examine the effects of RT on chronic low-grade inflammation in elderly adults through a systematic review and meta-analysis of randomized controlled trials (RCTs).

We included studies that assessed the effect of RT on C-reactive protein (CRP), interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α in those aged ≥60 years. The effect size was estimated using fixed or random-effects models. Subgroup analysis was performed regarding age, health status, training method, number of exercises, intensity, weekly frequency, and duration. In the 18 randomized controlled trials (539 patients) included, RT was effective in alleviating CRP, IL-10, and TNF-α in elderly adults and tended to reduce IL-6. Subgroup analyses showed CRP reduction regardless of age, training method, number of exercises, intensity, weekly frequency, and duration. RT can be used to ameliorate chronic low-grade inflammation in elderly adults.

Link: https://doi.org/10.3390/ijerph19063434

A fairly broad effort is underway to make small molecule drug discovery faster, cheaper, and less onerous by employing machine learning strategies. Implementations of this and related approaches are common in the growing longevity industry, for reasons that may have to do with the overlap of interests in longevity and artificial intelligence in the Bay Area entrepreneurial and venture communities, where it is comparatively common for people to make the leap from the software industry to biotechnology, and look for ways to apply their existing skills to a new industry.

A number of drug development platform companies have at least started out with a focus on aging, such as Insilico Medicine, BioAge, and so forth. If you are curious about how one goes about accelerating small molecule drug discovery in this way, look no further than this open access paper, which discusses some of Insilico Medicine's recent work in enough detail to get a taste of it.

Aging biology is a promising and burgeoning research area that can yield dual-purpose pathways and protein targets that may impact multiple diseases, while retarding or possibly even reversing age-associated processes. One widely used approach to classify a multiplicity of mechanisms driving the aging process is the hallmarks of aging. In addition to the classic nine hallmarks of aging, processes such as extracellular matrix stiffness, chronic inflammation, and activation of retrotransposons are also often considered, given their strong association with aging.

In this study, we used a variety of target identification and prioritization techniques offered by the AI-powered PandaOmics platform, to propose a list of promising novel aging-associated targets that may be used for drug discovery. We also propose a list of more classical targets that may be used for drug repurposing within each hallmark of aging. Most of the top targets generated by this comprehensive analysis play a role in inflammation and extracellular matrix stiffness, highlighting the relevance of these processes as therapeutic targets in aging and age-related diseases.

Overall, our study reveals both high confidence and novel targets associated with multiple hallmarks of aging and demonstrates application of the PandaOmics platform to target discovery across multiple disease areas.

Link: https://doi.org/10.18632/aging.203960

When looking at epidemiological evidence of the burden of amyloid-β and phosphorylated tau in the aging brain, and relating it to incidence and degree of neurodegenerative disease, it is worth bearing in mind that this doesn't demonstrate causation. It remains the case that amyloid-β aggregation could be peripheral to the progression of Alzheimer's disease, a side-effect of the primary mechanism, which could be something along the lines of chronic inflammation driven by cellular senescence or chronic inflammation driven by persistent infection by herpesviruses or the like.

That amyloid-β has been cleared in clinical trials without showing much benefit to patients could arise for many different reasons: that it is only important to pathology in early stages; that it is not important at all; that vascular issues and other problems present in many Alzheimer's patients would also need repair in order to see benefits; and so forth. This is one of the challenges inherent in dealing with complex end-stage age-related diseases. They have a number of potential contributing causes and the only viable way to understand which of those causes are actually important is to address them. Further, it is quite possible that given a set of equally important causes, addressing any one of them on its own may appear to fail.

Current Findings Give Backing to Anti-Amyloid Therapies

In the course of Alzheimer's disease, two proteins called amyloid and tau accumulate in the brain. A study with more than 200 participants now provides insights into the interaction of these pathological phenomena. The data suggest that tau load in the brain impairs memory functions only when amyloid burden is also high. These findings therefore support therapeutic approaches aimed at removing amyloid from the brain in the early stages of Alzheimer's disease.

"It has long been known that deposits of tau proteins in the hippocampus and in neighboring brain areas impair memory. In the case of amyloid, on the other hand, no clear relationship to memory performance has been found to date. For this reason, among others, it is debated whether it makes sense at all to target amyloid therapeutically. Our current results suggest that this could indeed be helpful for memory function in the early stages of the disease. The crucial aspect is that you don't look at tau in isolation, but together with amyloid pathology. This is where a link becomes apparent when you study a larger number of individuals and accordingly have solid statistics."

Amyloid pathology but not APOE ε4 status is permissive for tau-related hippocampal dysfunction

We investigated whether the impact of tau-pathology on memory performance and on hippocampal and medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF.

We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction, and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment.

There are, it is thought, enough people out there using rapamycin in the belief that it will meaningful slow aging to start a survey. The Impetus Grants project funded such a survey, to be conducted by academics already involved in the Dog Aging Project, also focused in part on the effects of rapamycin. As an mTOR inhibitor, rapamycin produces some of the same beneficial effects on metabolism and health as result from the practice of calorie restriction, meaning upregulated cell stress responses, particularly autophagy, and slowed aging - at least in mice, where this has been robustly studies. It remains an open question as to the size of the benefits in humans, but it one was going to spend time and funding on a way to modestly slow the aging process, then rapamycin is a far better choice than metformin, given a survey of the quality of the animal data.

Rapamycin is an mTOR inhibitor isolated from the Rapa Nui bacterium Streptomyces hygroscopicus. It is a well-established immune-modulating drug for use with transplant patients and has shown promising results on healthspan studies in laboratory animals. By collecting and disseminating data on several hundred people already taking low dose rapamycin for many months or years, this project will gather evidence for or against the use of rapamycin to improve health and prevent disease in people. At a minimum, this should largely resolve the current debate around safety of rapamycin use in this context.

Collected data will be analyzed primarily to assess common side effects experienced by patients (severity and frequency) in order to provide a true estimate of actual risk. Changes in medical or dental health from baseline will be assessed for each patient for whom that data is available. A summary of the overall cohort data will be published in a peer-reviewed journal.

Link: https://rapamycinstudy.org/

GM-CSF is a circulating cytokine that produces many different effects, and operates in both pro-inflammatory and anti-inflammatory contexts. Confusingly, one finds both delivery and inhibition of GM-CSF under development as therapies in different contexts. Here, researchers discuss its ability to improve memory function in aged mice, possibly by suppressing age-related inflammation in the brain, to be balanced against the point that raised GM-CSF is a feature of many inflammatory conditions. Further, it is worth considering that exercise, or indeed any form of improved blood flow to the brain, improves memory function at all ages. When looking at any new treatment, it makes sense to compare the magnitude of the effect with what can be achieved just by physical exercise. To be interesting, it should be significantly larger, a goal that remains a challenge in many areas of development.

A new study shows that a potential treatment for Alzheimer's disease may also improve cognitive function in people with Down syndrome. The drug sargramostim (recombinant GM-CSF, which stands for granulocyte-macrophage colony-stimulating factor) is the first to show memory improvement in Alzheimer's patients in a phase II clinical trial. GM-CSF is a normal human protein that is safe and well-tolerated with over 30 years of FDA-approved use for other disorders.

Researchers discovered that treatment with GM-CSF, which has pro-inflammatory, anti-inflammatory, and immune regulatory properties, reverses learning and memory deficits, the loss of certain nerve cells, and other abnormalities in the brain in a mouse model of Down syndrome and also improves cognition in normal aging mice.

The human version of GM-CSF/sargramostim has already been shown to be effective in improving cognition in people with mild-to-moderate Alzheimer's disease and in cancer patients. The findings support the hypothesis that GM-CSF/sargramostim may promote neuronal recovery from injury or from neurological disease through multiple mechanisms, some of which evidently enhance cognitive function.

Link: https://www.eurekalert.org/news-releases/947997

To open today's discussion, it is worth noting that any group that starts in on growing human clones that lack brains should expect to be promptly vilified and shut down by near any of the world's governments. The following discussion involves numerous projects that are already entirely illegal in most of the world. There is a very low tolerance for ethical experimentation with human tissue, unfortunately. That tolerance grows slowly over time, but we are certainly nowhere near the point at which entire bodies could be built in artificial wombs without a great deal of opposition at every step of the way.

It does seem worth talking about this prospect, however, because it is one of the technologically feasible approaches to evading the age-related failure of the body. Grow a clone without a brain, waiting the necessary years for it to be mature enough to use, transplant the old brain into the new cloned body, or transplant the head, a comparatively easier task, and then regenerate and connect the nervous system, vascular system, and all of the other items that pass through the neck into the head.

The long laundry list of capabilities needed to enact this course of action might be shorter than the list needed to repair the existing body, rejuvenating it. There may be less development and discovery required. I should say that this is not an assertion - it can be argued either way, and there is a great deal of uncertainty.

Firstly, there is the question of how to grow a new body without a brain, or at least without the parts of the brain that host a mind. This happens in the rare condition called anencephaly, a severe neural tube development disorder. The resulting body isn't a human, it is tissue without a mind. The causes are not fully understood, but researchers have looked at mutations in the MTHFR gene, with some compelling case studies. There is a path towards being able to create anencephaly to order in order to ethically grow mindless bodies.

Artificial wombs would be needed to generate replacement bodies at scale, and this is another field that in and of itself could be highly beneficial as a reproductive technology, but suffers its own restrictions on development. Researchers are thinking on the topic, however, and again there is a path forward given the present state of knowledge. The techniques needed to support brainless bodies after the initial development stage in an artificial womb are more of an unknown, given that natural anencephaly leads to rapid death after birth, but it seems plausible that many of the established techniques for brain dead and coma patients could be adapted to this use.

Separately, head transplantion in human patients is discussed in medical circles. It seems likely to happen at some point given the slow progression towards greater acceptance of procedures that provoke discomfort. If heart transplantation, why not body transplantation? Head transplantation has been carried out in animals, and there is a robust understanding of the challenges involved. The research community is a long way from what might be called reliability in producing a successful outcome, however. Further, the problems yet to be solved include producing a functional connection to the nervous system, a problem that might be analogous to that of repairing a severed spinal cord via regenerative therapies, or may be more complex due to individual differences in nervous system development.

Brain transplants are a much more speculative prospect. They have been carried out in primates, but the issues to be solved in moving a brain are manyfold more challenging and require a great deal more research and development. Nervous system tissue is fragile and non-regenerative. Still, given a focused program and significant funding, this is really just a matter of work, given where the research community stands today.

To my mind, the greatest objections to putting earnest effort into this line of work are that: (a) the damage of the aged brain will still need to be regenerated in some distinct way, restoring a youthful body will only go so far in term of restoring the environment; (b) major surgery in old age is highly undesirable, with a high risk of death through complications and stress; and (c) the expense of growing a body to sufficient maturity, for years, has the look of being very high in comparison to the expense of whole-body rejuvenation therapies. Rejuvenation of the brain will likely require technological capabilities that will enable rejuvenation of the body to a similar degree. So why not just aim in that direction to start with?

That said, the pieces of the replacement body puzzle are out there, waiting for someone to pull them together. Stranger things have happened.

Atherosclerosis is a consequence of macrophage dysfunction. Macrophages are innate immune cells that help to remove excess cholesterol from blood vessel walls; cholesterol is primarily manufactured in the liver, and must travel through the bloodstream on LDL particles to reach the rest of the body. Macrophages help to retrieve unwanted cholesterol and return it to the bloodstream, attaching it to HDL particles for a return to the liver and excretion. This all works just fine in youth, but with age macrophages become inflammatory and dysfunctional, overwhelmed by cholesterol and the aged tissue environment, failing at their tasks and ultimately dying. This leads to growing fatty lesions in blood vessel walls, inflammatory macrophage graveyards that call in more immune cells to their deaths. Ultimately, one of these lesions ruptures, causing a heart attack or stroke. This kills more than a quarter of humanity.

Macrophages are large white blood cells that cruise through our body as a kind of clean-up crew, clearing hazardous debris. But in people with atherosclerosis - fatty deposits and inflammation in their blood vessels - macrophages can cause trouble. They eat excess fat inside artery walls, but that fat causes them to become foamy. And foamy macrophages tend to encourage inflammation in the arteries and sometimes bust apart plaques, freeing clots that can cause heart attack, stroke, or embolisms elsewhere in the body.

Changing how macrophages express a certain protein could prevent that kind of bad behavior. Researchers found that the protein, called TRPM2, is activated by inflammation. It signals macrophages to start eating fat. Since inflammation of the blood vessels is one of the primary causes of atherosclerosis, TRPM2 gets activated quite a bit. All that TRPM2 activation pushes macrophage activity, which leads to more foamy macrophages and potentially more inflamed arteries.

Researchers demonstrated one way to stop the cycle, at least in mice. They deleted TRPM2 from a type of lab mouse that tends to get atherosclerosis. Deleting that protein didn't seem to hurt the mice, and it prevented the macrophages from getting foamy. It also alleviated the animals' atherosclerosis. Researchers are now looking at whether increased TRPM2 expression in monocytes (circulating precursors of macrophages) in the blood correlates with severity of cardiovascular disease in humans.

Link: https://today.uconn.edu/2022/03/deleting-a-protein-in-mice-prevents-cardiovascular-disease/

Short-lived killifish are one of the more recently adopted animal models of aging. All such models are a trade-off between the cost of running studies and the relevance of their biochemistry to long-lived mammals such as our own species. Fortunately, a lot of the cellular biochemistry of aging is similar enough to make such models useful; unfortunately the differences are often significant enough to sink specific attempts to discover mechanisms and build new therapies. Here, researchers look at the aging immune system in killifish, finding a feature known to exist in humans, and further digging in to the details.

Aging individuals exhibit a pervasive decline in adaptive immune function, with important implications for health and lifespan. Previous studies have found a pervasive loss of immune repertoire diversity in human peripheral blood during aging; however, little is known about repertoire aging in other immune compartments, or in species other than humans. Here, we perform the first study of immune repertoire aging in an emerging model of vertebrate aging, the African turquoise killifish (Nothobranchius furzeri). Despite their extremely short lifespans, these killifish exhibit complex and individualized heavy-chain repertoires, with a generative process capable of producing millions of distinct productive sequences.

Whole-body killifish repertoires decline rapidly in within-individual diversity with age, while between-individual variability increases. Large, expanded B-cell clones exhibit far greater diversity loss with age than small clones, suggesting important differences in how age affects different B-cell populations. The immune repertoires of isolated intestinal samples exhibit especially dramatic age-related diversity loss, related to an elevated prevalence of expanded clones. Lower intestinal repertoire diversity was also associated with transcriptomic signatures of reduced B-cell activity, supporting a functional role for diversity changes in killifish immunosenescence. Our results highlight important differences in systemic vs. organ-specific aging dynamics in the adaptive immune system.

Link: https://doi.org/10.7554/eLife.65117

The urge to create taxonomies is very human, almost reflexive. We make lists, divide things up into buckets and categories. I'm not entirely convinced that there is yet the need to do this when it comes to personal efforts to slow or reverse aging, but that opinion certainly isn't going to stop people from publishing their thoughts on the matter. Today's open access paper is an example, in which a few arbitrary lines in the sand are drawn, and the spectrum of present day efforts to live longer is divided into five broad categories.

The one point that makes it, I think, hard to take any given taxonomy seriously is that we do not yet know how well the various options presently on the table perform in humans. There is reasonable support for the supposition that anything to do with stress response upregulation, such calorie restriction mimetic therapies, may be beneficial. Even if robustly so, however, as a strategy it is likely not going to be much better than good lifestyle choices. Some of those calorie restriction mimetics are unimpressive even given that caveat, such as aspirin and metformin. Similarly there is reasonable support for senolytics that clear senescent cells to be a very desirable medical technology, capable of much more than lifestyle choices can achieve.

It will be years yet before any of these suppositions are validated in human trials to the satisfaction of conservative minds, however, and years more before researchers can put actual numbers to the effects on human life span, given our length of life. Thus any taxonomy that takes into account efficacy might be premature. Still, we have to make decisions about which strategies to pursue in some way.

The intervention on aging system: A classification model, the requirement for five novel categories

The longevity industry has now entered a new era, where various longevity technologies are being used by a growing cohort of subjects worldwide. As humanity enters this new era, subjects and their healthcare advisors, even employers such as military or insurance companies may require a classification system to assist in understanding what therapies should be implemented (or avoided) at what time during life. A simplistic classification system with five classes enables the public to easily see where they sit on a mortality scale and may provide motivation to change their lifestyle. This system is inversely proportional to mortality: the higher your class, the more probable you are to develop disease or undergo loss of life.

Type V - The Type 5 category perform rudimentary functions to maintain life, such as washing hands and using seatbelts in cars; however, their diet includes fast food and occasional healthy food, these subjects may hold excessive weight, and overall, they do very little to extend their life or health span. Mortality Risk - Probable.

Type IV - The Type 4 demographic exercise and eat relatively healthy and may use health supplements. Type 4's attempt to navigate away from toxins such as cigarettes, perform weight management, and may restrict or abstain from alcohol though do not implement any emerging or significant longevity technologies or regimes such as fasting or clean plant-based diets. Mortality Risk - Moderate.

Type III - The Type 3 class is proactive in using anti-aging technologies, they actively seek and study longevity for increased awareness, they use nicotinamide adenine dinucleotide precursors to maintain cellular metabolism and foods specifically known for their anti-aging properties, they possibly practice fasting, use fasting mimetics, exercise and are lean or muscular, target a more epigenetic diet, and steer clear of any biological insults. Mortality Risk - Unlikely.

Type II - The Type 2 cohort implement a strict longevity lifestyle that is very similar to Type 3's; however, Type 2's also implement early disease prevention strategies such as whole genome sequencing, whole exome sequencing, gene panel, single gene testing, and methylation analysis to garner data on their disease predisposition and penetrance. Other testing such as glycomic testing, blood plasma, and proteomic testing and other biomarkers that can assist in predicting and in some cases preventing disease are also used. Mortality Risk - Low.

Type I - Type 1's encompass everything that Type 2's perform; however, Type 1's have achieved a status of disease prevention and developed strategies to prevent further biological decay through various lifestyle decisions, including full spectrum diagnostic services, gene editing, and tissue reprogramming, and immune system or thymic rejuvenation to ensure high resistance to disease and dysfunction.

The scale shown here clearly demonstrates that there are various stages to longevity management that are completely distinguishable between one another. A classification system such as this also paves the way for governments to set goals and targets for their aging populations. Even though Type I status is not yet achievable, the scale intentionally includes this category, not only for future use, but as a symbol for humanity's scientific vision and quest to deliver a disease-free and much healthier society.

Degenerative disc disease is commonplace, and in recent years research has implicated the age-related accumulation of senescent cells in the onset and progression of this condition. Senolytic drugs to clear senescent cells may thus be a useful treatment. Existing senolytics, such as the dasatinib and quercetin combination, could be applied to many age-related conditions, since senescent cells and their inflammatory secretions produce broad negative effects on cell and tissue function. Unfortunately there is little funding and financial incentive for academic organizations to run clinical trials for even a significant fraction of these conditions.

Intervertebral disc degeneration (IVDD) refers to an age-related change that mainly occurs in the lumbar intervertebral disc and often precedes other age-related changes. During the process of IVDD, annulus fibrosis (AF), one of the important compositions of intervertebral disc, loses its original layer and toughness, and reticulated degeneration and hyalinization appear, while the percentage of water decreases in another component called nucleus pulposus (NP). As a result, the intervertebral disc loses its normal elasticity and tension.

Aging is the primary risk factor for the development of IVDD, which causes the accumulation of senescent cells in the intervertebral disc. Researchers have found that senescent NP cells play an important role in the initiation of IVDD. The number of senescent NP cells increased significantly during IVDD, suggesting the deleterious effect of senescent NP cells on the pathogenesis of IVDD. Recent studies have shown that senescent cells could secrete metabolic factors such as pro-inflammatory cytokines, matrix-degrading proteases, growth factors://en.wikipedia.org/wiki/Growth_factor">growth factors, and chemokines, which caused changes of the extracellular matrix (ECM). In addition, senescent cells can affect adjacent cells through paracrine signaling, thereby inducing the catabolism and inflammation in the microenvironment of intervertebral disc. The metabolic factors secreted by senescent cells are collectively named senescence-associated secretory phenotype (SASP).

In recent years, investigations on new drugs that target the process of senescence have become a new therapeutic strategy for the early prevention and latter treatment for degenerative diseases. Evidence suggest that whether through genetically modified strategy or chemotherapy, the elimination of p16INK4a senescent cells has been shown to significantly extend the healthspan in murine models. So, optimizing treatments to reduce senescence or eliminate senescent cells may exert positive effects on human health. Senolytic represents a wide range of drugs or small molecules that can selectively eliminate senescent cells. The application of senolytic drugs is a potential strategy for degenerative disease treatment, including IVDD.

Link: https://doi.org/10.3389/fbioe.2022.823945

Autophagy is the name given to a collection of cellular housekeeping processes that recycle damaged and otherwise unwanted proteins and structures in the cell. Increased autophagy is a common feature of interventions that alter metabolism and slow aging in short-lived species. This is well studied in the context of calorie restriction, and is likely an important mechanism in mTOR inhibition, such as via rapamycin. Still, the only really impressive results produced via upregulation of autophagy to date are in the liver, starting with the use of LAMP2A as a target to improve operation of the lyosomal portion of autophagy in aged animals. In that context, it is interesting to take a look at what is known of aging at the detail level in liver tissue.

During aging, the liver undergoes a series of degenerative changes. Briefly, it presents a progressive decrease in functional liver mass, thus reducing its functional reserve, making it more difficult to maintain homeostasis and vulnerable to external stress or damage. Till now, the mechanisms underlying liver aging still remain unclear. As we known, the main causes of aging are DNA damage, telomere shortening, epigenetic alterations, and impairment of proteostasis.

The aged liver is usually accompanied with failure of regeneration, metabolic dysfunction, redox imbalance, and development of chronic or malignant liver diseases. The impairment of regenerative capacity in the aged liver is affected by both intracellular factors and extracellular factors. Intriguingly, we may be able to recover their regenerative capacity via changing a microenvironment for the senescent hepatocytes. The aging-related alterations in the liver form a unique microenvironment and affect a series of physiological processes. Moreover, this unique microenvironment may function as a vital role that causes the liver to become susceptible to chronic diseases or tumors. For instance, it affects the fate of hepatocytes and promotes neoplastic development. Moreover, hepatocytes in this microenvironment are more susceptible to ischemia/reperfusion (I/R) injury.

Of particular interest is the way to effectively eliminate the effects of aging and reverse the unique aging microenvironment in the aged liver. Modulation of autophagy could function as an effective strategy for reversing aging in the liver. Autophagy mainly functions as a cytoprotective role in liver diseases. Modulation of autophagy could markedly alleviate aging-related liver injury, promote liver regeneration, block I/R induced injury, and reverse the aging microenvironment in the aged liver.

Link: https://doi.org/10.3389/fmed.2022.842024