Fight Aging!

The important point made by the authors of today's open access paper is that, in the matter of epigenetic clocks, the focus of the research community should shift from the production of ever more refined clocks that better correlate with chronological age, biological age, or specific manifestations of aging, to attempts to understand how exactly the mechanisms and dysfunctions of aging determine change in these clocks. This is now well understood in most parts of the research community, but it still has to be said, and often.

The real promise of epigenetic clocks, and clocks built on transcriptomic, proteomic, and other similar data, is to make the assessment of potential rejuvenation therapies a rapid and cost-effective process. Simply run the clock before and after the treatment, a very favorable alternative to the lengthy studies that are the only present alternative. Without an understanding of which biological processes the clock reflects, however, that data can't be trusted until that specific clock is calibrated against the specific therapeutic approach with slow, expensive lifespan studies. Perhaps the clock undervalues some mechanisms of aging and overvalues others. At present no-one knows whether or not this is the case for any given clock. This state of affairs is a roadblock for the goal of speeding up the process of research and development.

Epigenetic aging: Biological age prediction and informing a mechanistic theory of aging

Nearly a decade ago, researchers showed that a large number of CpG sites in the human genome increase or decrease in methylation fraction over time, such that one can select among these CpG sites to measure the rate at which an individual ages. These so-called "epigenetic clocks" train regularized linear regression models to predict the chronological age of an individual from the methylation values of CpG sites distributed across the genome. During training, the CpG sites for which the methylation fractions are most predictive of chronological age are identified and selected for use in the linear regression equation. The number of CpG sites selected has depended greatly on the particular approach used but is typically between two and a few hundred.

In the time since these epigenetic clocks were introduced, substantial development effort has been invested into improving their predictive accuracy and extending their range of applications. The first randomized clinical trial using an epigenetic clock as the main validator of intervention efficacy was recently conducted. The prediction of epigenetic age has also been made more accessible and efficient; epigenetic clock software packages are readily available, with some requiring methylation values at only a few CpG sites for accurate age predictions. The sophistication of epigenetic clocks today is greater than it was a decade ago because the tools have broader reach, and we fully expect this trend to continue.

While optimization of existing concepts and methods is important, it is also vital that the field keeps moving. Beyond the construction of increasingly accurate chronological clocks, there are many unanswered questions related to the specific mechanisms by which the epigenome influences aging and, reciprocally, by which aging influences the epigenome. Prediction of age was an important first step, but - in our view - the focus must shift from chasing increasingly accurate age computations to understanding the links between the epigenome and the mechanisms and physiological changes of aging.

You might recall that an approach to reversing presbyopia by breaking a type of cross-link in the lens of the eye is in the fairly late stages of development. Cross-links stiffen the lens, making it hard to focus properly because the muscles of the eye are no longer able to produce enough force to obtain the desired result. The founders of a new company, Lento Bio, plan to do much the same thing for a different set of cross-link targets in the lens, those based on advanced glycation end-products, with the hope of improving upon the promising results already obtained via this strategy.

Lento Bio, Inc., a preclinical pharmaceutical company focused on developing small molecule therapeutics to target molecular damage driving age-related disease, announced its launch today. The company will initially focus on developing pharmaceutical eyedrops to treat a common vision disorder, presbyopia, or age-related farsightedness. Lento Bio will be supported and incubated by Ichor Life Sciences, a pre-clinical contract research organization, at Clarkson University's Peyton Hall Biotechnology Incubator.

Presbyopia is caused by stiffening of the eye lens, which stems from molecular crosslinks including advanced glycation end products (AGE) that cause tissue rigidity. The small molecule drugs being developed by Lento Bio will target underlying molecular damage accumulation with the goal of reversing the process of tissue-stiffening in the ocular lens. Upon successful completion of its first project, Lento Bio plans to apply its anti-glycation products more widely to include systemic diseases of aging.

"Lento Bio is starting from a solid foundation of established research into molecular aging damage and will focus development efforts towards the most accessible and relevant disease indications. Through bringing the problem to the science we aim to accelerate the creation of clinical assets and validate our disease hypothesis. We look forward towards collaborating with the scientific teams at Ichor and Clarkson University to pursue research and development of small molecule drugs."

Link: https://ichorlifesciences.com/2022/06/lento-bio/

The gut microbiome changes with age, in part because the immune system falters in its task of removing harmful microbes. Microbial populations responsible for producing beneficial metabolites decline in number, while populations that provoke chronic inflammation and other harms grow in number. Researchers are only just beginning to catalog the long list of harmful outcomes produced by an aged gut microbiome. The open access paper here is an example of this research, using mice to demonstrate a connection between the gut microbiome and hippocampal function in the brain, essential to memory.

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain yet highly debated. Here we showed that fecal microbiota transplantation (FMT) from aged, but not young, animal donors in young mice is sufficient to trigger profound hippocampal alterations including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors.

To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve (VN)-related neuronal activity patterns and report that aged-mice FM transplanted animals showed a reduction in neuronal activity in the ascending VN output brain structure, whether under basal condition or after VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mice FMT on hippocampal functions, and had a detrimental effect on memory in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.

Link: https://doi.org/10.1172/jci.insight.147700

A growing body of academic work is focused on the activity of transposable elements in degenerative aging, and some of these projects may produce approaches to therapy based on suppressing this activity. Transposable elements are DNA sequences capable of copying themselves within the genome, thought to be the result of ancient viral infections, but which contribute to evolution by providing a ready path to mutational change. Transposable elements are suppressed in youth, but with age the regulation of gene expression becomes more ragged, and transposable elements exhibit ever greater activity. This is supposed by many researchers to contribute to degenerative aging in much the same way as other stochastic mutational damage, though proving this is ever a challenge, and also via provoking chronic innate immune responses to what might look like viral activity.

There are several categories of transposable element, one of which, the retroviruses, is the topic of today's open access paper. The researchers assess the evidence for one particular pathway to be responsible for ensuring that retrovirus activation in older individuals produces an inflammatory response. As more researchers engage with the question of the role of transposable elements in aging, we'll see more research directed at potential target mechanisms that might be used to suppress transposable element activity in later life. Suppressing transposable element activity is the right way forward to determine just how much damage is being caused by this age-related failure to control the replication of transposable elements, to determine just how much of an influence this process has on degenerative aging. In matters relating to aging, fixing a given mechanism is really the only way to assess the degree to which that specific mechanism is hurting us all.

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

Transposable elements (TE) make up about 46% of the human genome. They consist in repetitive sequences which are capable to or potentially capable to actively or passively insert copies of themselves elsewhere in the genome. TE are classified in Class I TEs, if they are RNA retrotransposons that require reverse transcriptase activity for transposition, and Class II TEs, or DNA transposons, that require transposase enzyme for their mobilization. LINE (long interspersed nuclear elements) and SINE (short interspersed nuclear elements) are the most studied and abundant class I TEs. The third family of Class I TEs consists of long terminal repeat (LTR) retroelements, known as HERVs (human endogenous retroviruses). HERV are residues of viral infections from the past that have remained in the human genome and occupy about 8% of it.

Bi-directional transcription of hERVs is a common feature of autoimmunity, neurodegeneration, and cancer. Higher rates of cancer incidence, neurodegeneration, and autoimmunity but a lower prevalence of autoimmune diseases characterize elderly people. Although the re-expression of hERVs is commonly observed in different cellular models of senescence as a result of the loss of their epigenetic transcriptional silencing, the hERVs modulation during aging is more complex, with a peak of activation in the sixties and a decline in the nineties. What is clearly accepted, instead, is the impact of the re-activation of dormant hERV on the maintenance of stemness and tissue self-renewing properties.

An innate cellular immunity system, based on the RLR-MAVS circuit, controls the degradation of double-stranded DNAs arising from the transcription of hERV elements, similarly to what happens for the accumulation of cytoplasmic DNA leading to the activation of cGAS/STING pathway. While agonists and inhibitors of the cGAS-STING pathway are considered promising immunomodulatory molecules, the effect of the RLR-MAVS pathway on innate immunity is still largely based on correlations and not on causality. Here we review the most recent evidence regarding the activation of MDA5-RIG1-MAVS pathway as a result of hERV de-repression during aging, immunosenescence, cancer, and autoimmunity. We will also deal with the epigenetic mechanisms controlling hERV repression and with the strategies that can be adopted to modulate hERV expression in a therapeutic perspective. Finally, we will discuss if the RLR-MAVS signalling pathway actively modulates physiological and pathological conditions or if it is passively activated by them.

A great deal of time and effort was required to achieve the first pig to human heart transplant, including the production of genetically engineered pigs that lack the cell features that provoke rejection, and which minimize the presence of porcine viruses. Nonetheless, the first transplanted heart failed after some weeks for reasons that are yet to be determined, undergoing widespread cell death. This suggests that the remainder of the path towards viable xenotransplantation will be longer than hoped. As a strategy, xenotransplantation competes with work on the production of organs built from patient cells, an approach that will likely take at least as long to be realized.

The pig that served as the heart donor came from a population that has been extensively genetically engineered to limit the possibility of rejection by the human immune system. The line was also free of a specific virus that inserts itself into the pig genome (porcine endogenous retrovirus C, or PERV-C) and was raised in conditions that should limit pathogen exposure. The animal was also screened for viruses prior to the transplant, and the patient was screened for pig pathogens afterward.

While patient weight loss was a concern, at five weeks after the transplant, there were no indications of rejection, and the heart was still functioning. Things started to go bad about seven weeks post-transplant when the patient's blood pressure began to drop. Fluid started building on his lungs, and he had to be intubated. Imaging showed that his heart was still clearing out most of the volume of the ventricles with each beat, but the total volume had shrunk as the walls of the ventricle thickened. Eventually, external oxygenation had to be restarted.

Pig DNA began to show up in the bloodstream, indicating tissue damage; some anti-pig-cell antibodies were also detected, suggesting a degree of rejection. But a biopsy failed to find any signs of it in the heart tissue; instead, there were signs that capillaries in the heart were leaking, creating swelling and allowing blood cells into the heart tissue. A week later, a second biopsy indicated that about 40 percent of the heart muscle cells in the transplant were dead or dying, even though there were still no indications of rejection in the tissue. That level of damage brought an end to things and life support was withdrawn.

Link: https://arstechnica.com/science/2022/06/pig-heart-transplant-failed-as-its-heart-muscle-cells-died/

One should always be somewhat dubious when researchers claim the primacy of any single mechanism in age-related dysfunction. It is one thing to demonstrate that a mechanism exists and is damaging, and quite another to show that it provides a significant contribution to aging in animal models or humans. Aging is enormously complex, and it has traditionally proven very challenging to repair or ameliorate just one mechanism in isolation, in order to see what happens. Bear this in mind while reading this otherwise interesting paper on the function of ALCAT1 in age-related mitochondrial dysfunction.

Cardiolipin (CL) is a mitochondrial signature phospholipid that plays a pivotal role in mitochondrial dynamics, membrane structure, oxidative phosphorylation, mitochondrial DNA bioenergetics, and mitophagy. The depletion or abnormal acyl composition of CL causes mitochondrial dysfunction, which is implicated in the pathogenesis of aging and age-related disorders. However, the molecular mechanisms by which mitochondrial dysfunction causes age-related diseases remain poorly understood.

Recent development in the field has identified acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1), an acyltransferase upregulated by oxidative stress, as a key enzyme that promotes mitochondrial dysfunction in age-related diseases. ALCAT1 catalyzes CL remodeling with very-long-chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). Enrichment of DHA renders CL highly sensitive to oxidative damage by reactive oxygen species (ROS). Oxidized CL becomes a new source of ROS in the form of lipid peroxides, leading to a vicious cycle of oxidative stress, CL depletion, and mitochondrial dysfunction. Consequently, ablation or the pharmacological inhibition of ALCAT1 have been shown to mitigate obesity, type 2 diabetes, heart failure, cardiomyopathy, fatty liver diseases, neurodegenerative diseases, and cancer.

The findings suggest that age-related disorders are one disease (aging) manifested by different mitochondrion-sensitive tissues, and therefore should be treated as one disease. This review will discuss a unified hypothesis on CL remodeling by ALCAT1 as the common denominator of mitochondrial dysfunction, linking mitochondrial dysfunction to the development of age-related diseases.

Link: https://doi.org/10.3390/cells11121906

The immune system becomes ever more inflammatory with advancing age, a state known as inflammaging, even as it loses competence in destroying pathogens and unwanted cells. This sustained, unresolved inflammation is harmful, the cause of numerous harmful changes in cell function and failures of tissue maintenance. It accelerates the onset and progression of all of the common age-related conditions. This is caused in part by the pro-inflammatory signaling of senescent cells, present in increasing numbers in the aged body. Another important contribution, and a focus in today's open access paper, is the activation of innate immune cells by signs of cell dysfunction and damage such as DNA debris. These are known as damage associated molecular patterns (DAMPs), and their presence is characteristic of aging, provoking the innate immune system into overactivation.

What can be done to minimize inflammaging? Blocking specific inflammatory signals can reduce inflammation, as established therapies for autoimmune conditions demonstrate, but at the cost of further reducing the effectiveness of the immune system. This type of strategy blocks both necessary and excessive inflammation. Compare this with removal of senescent cells via senolytic therapies, an approach that does only remove the excessive inflammatory signaling. Is it possible to remove DAMPs, and thereby prevent activation of the innate immune system? Not at present. The only practical way to reduce DAMPs is to modestly slow aging as a whole, achieved via life-long strategies such as calorie restriction. We can hope that progress will be made towards better approaches in the years ahead, but this sort of strategy is not a focus in today's research community.

Inflammaging is driven by upregulation of innate immune receptors and systemic interferon signaling and is ameliorated by dietary restriction

A prominent aging-associated condition is a chronic inflammation referred to as "inflammaging," a pro-inflammatory phenotype that accompanies aging in mammals. Inflammaging is a highly significant risk factor for most, if not all, aging-related diseases including obesity and type 2 diabetes, cardiovascular diseases, Alzheimer's disease, and cancer, as well as vulnerability to infectious disease and vaccine failure.

Dietary restriction (DR) decreases the calorie intake without inducing malnutrition. Lifetime DR is a non-pharmacological intervention that can extend the lifespan in a wide range of organisms. It has been shown that long-term DR (LTDR) also reduces some aspects of inflammation, leading to the hypothesis that a life-long energy accumulation can be the origin of chronic inflammation. A very recent study carried out in rats has shown that late-life DR attenuated aging-related changes in cell type composition and gene expression, and reversed the aging-associated increase of senescence markers and alterations of the immune system. However, it is still largely unknown which signaling pathways and networks regulate the induction of inflammaging across tissues and whether DR could have an impact on rescuing such systemic induction of inflammaging.

In this study we employ a transcriptome-wide and multi-tissue approach to analyze the influence of both LTDR and short-term DR (STDR) at old age on the aging phenotype. We were able to characterize a common transcriptional gene network driving inflammaging in most of the analyzed tissues. This network is characterized by chromatin opening and upregulation in the transcription of innate immune system receptors and by activation of interferon signaling through interferon regulatory factors, inflammatory cytokines, and Stat1-mediated transcription. We also found that both DR interventions ameliorate this inflammaging phenotype, albeit with some differences mainly at tissue-specific level. Further chromatin accessibility analysis showed that DR can also rescue the aging-associated epigenetic alteration on the inflammaging-related genes, but not the genome-wide impairment of chromatin that accompanies old cells.

In this study, we showed that aging changed the transcriptome of different tissues and that DR was able to partially rescue the age transcriptome. DR intervention in late life has been recently shown to not provide as beneficial effects as long-life DR in lifespan and healthspan extension. For this reason, we compare old mice with mice treated with both a lifetime DR (LTDR) and a short-term DR at late life (STDR). We found that responses to the aging, LTDR, and STDR both in magnitude and functional aspects were tissue specific. LTDR has been previously shown to strongly prevent a pro-inflammatory phenotype in aged white adipose tissue pre-adipocytes, whereas a late-onset DR failed in preventing it. Our data show that LTDR was more effective in rescuing inflammaging in liver and kidney, while STDR mitigated aging-associated activation of inflammatory pathways more effectively in blood; in other tissues both LTDR and STDR prevented the pro-inflammatory phenotype to a similar extent.

The dominant cancer therapies of chemotherapy and radiotherapy have not yet been replaced by immunotherapies for more than a handful of cancer types. These classes of therapy produce a significantly increased burden of senescent cells in patients; one of the goals of cancer therapy is to drive cancerous cells into senescence, those that cannot be killed. These additional senescent cells in turn accelerate the progression of degenerative aging. The advent of senolytic therapies to clear senescent cells from aged tissues will make a sizable difference to these patients. More effort should be undertaken today to enable patient access to the existing, low-cost first generation senolytics, such as the dasatinib and quercetin combination.

A new study found that adult survivors of cancer had a 42% greater risk of cardiovascular diseases (CVD) than people without cancer. The authors found that survivors of cancer had a particularly higher risk of developing heart failure (52% higher risk), followed by stroke (22% higher risk). There were no significant differences in the risk of coronary heart disease between those with and without cancer.

The analysis used data from the Atherosclerosis Risk in Communities Study, a prospective community-based population study, initiated in 1987, of CVD and its risk factors. The study had 12,414 participants, with a mean age of 54 who were followed through 2020. Although the study was not designed to pinpoint the causes of increased CVD risk among survivors of cancer, the main hypothesis involves a combination of cancer and noncancer related factors such as inflammation, oxidative stress, cardiac toxicity from specific cancer treatments, and traditional risk factors like hypertension, diabetes, and obesity. While the excess risk of CVD in this group was not fully explained by traditional cardiovascular risk factors such as obesity, high blood pressure and cholesterol levels, and diabetes, it is still very important to address these risk factors that are common in survivors of cancer.

Cardiac toxicity from cancer therapies, or negative cardiac effects of cancer therapies, may be particularly important in increasing the risk of CVD in some survivors of cancer. For example, survivors of breast and blood cancers had significantly higher risk of CVD, and these cancers are typically managed with a combination of chemotherapy and chest radiation that can damage the heart. Conversely, survivors of prostate cancer did not have an increased risk of CVD. These patients can be managed with active surveillance or local therapies without the risk of cardiac toxicity.

Link: https://www.eurekalert.org/news-releases/957222

This review paper provides an overview of what is known and theorized of the influence of the gut microbiome on the aging of the vasculature. Cardiovascular disease is the largest cause of human mortality, and there is considerable interest in better understanding how to slow its onset, given the lack of progress towards meaningful reversal of conditions such as atherosclerosis. The relative abundance of populations in the gut microbiome change with age in ways that (a) diminish the production of beneficial metabolites, and (b) provoke chronic inflammation. It is most likely primarily this latter point that drives issues in the vasculature, given the strong evidence for chronic inflammation to drive the progression of cardiovascular disease. That said, as noted here, direct correlations between the microbiome and some of the preferred measures of vascular aging have yet to be established, or are not in evidence.

The gut microbiota is a critical regulator of human physiology, deleterious changes to its composition and function (dysbiosis) have been linked to the development and progression of cardiovascular diseases. Vascular ageing (VA) is a process of progressive stiffening of the arterial tree associated with arterial wall remodeling, which can precede hypertension and organ damage, and is associated with cardiovascular risk. Arterial stiffness has become the preferred marker of VA.

In our systematic review, we found an association between gut microbiota composition and arterial stiffness, with two patterns, in most animal and human studies: a direct correlation between arterial stiffness and abundances of bacteria associated with altered gut permeability and inflammation; an inverse relationship between arterial stiffness, microbiota diversity, and abundances of bacteria associated with most fit microbiota composition.

Interventional studies were able to show a stable link between microbiota modification and arterial stiffness only in animals. None of the human interventional trials was able to demonstrate this relationship, and very few adjusted the analyses for determinants of arterial stiffness. We observed a lack of large randomized interventional trials in humans that test the role of gut microbiota modifications on arterial stiffness, and take into account blood pressure and hemodynamic alterations.

Link: https://doi.org/10.3390/jcm11123557

Senescent cells serve many purposes in the body, such as aiding in wound healing and suppression of cancer, but they become harmful when present in significant numbers for an extended period of time. This occurs with age, as the immune system becomes less effective at its task of clearing those senescent cells that fail to undergo programmed cell death. As senescent cells are created constantly, when somatic cells hit the Hayflick limit on replication, and to a lesser degree in response to molecular damage, a slowing of clearance leads to an accumulation of these errant cells. Senescent cells secrete a mix of signals, the senescence-associated secretory phenotype (SASP), that, when present over the long term, provokes harmful inflammation, restructuring of the extracellular matrix, and detrimental changes in cell behavior.

Atherosclerosis is an inflammatory condition, in which fatty deposits form in artery walls due to the dysfunction of the macrophage cells responsible for removing that damage. More inflammatory signaling makes matters worse, by both changing the behavior of macrophages, and calling in more macrophages to swell the mass of the atherosclerotic plaque. That is enough on its own to consider targeting senescent cells for destruction, to remove their inflammatory signaling as a way to slow the growth of plaque. Today's open access paper adds a few other concerns, such as the way in which senescent cells may be disruptive of the protective fibrosis that helps stabilize soft plaques.

There is good reason to think that senolytic therapies to selectively destroy senescent cells may be beneficial in the context of atherosclerosis, or indeed in any age-related condition with a strong connection to chronic inflammation, but not all senolytics may effectively target the relevant senescent populations, or localize sufficiently to the arteries, as noted in the paper here. The question of whether senescent cells provide a major contribution or a minor contribution to the progression of atherosclerosis remains open, though the early attempts to produce benefits in animal models have not been promising. If that state of affairs continue, then attention must return to other pathological mechanisms.

Senescence in Vascular Smooth Muscle Cells and Atherosclerosis

Vascular smooth muscle cells (VSMCs) are the primary cell type involved in the atherosclerosis process; senescent VSMCs are observed in both aged vessels and atherosclerotic plaques. Cellular senescence is not a static cellular state, but a dynamic process during which cells undergo quiescence (initial transient senescence), early senescence (stable growth arrest), complete senescence (chromatin changes associated with senescence and SASP), and late/deep senescence (phenotypic diversification). Similar to other cell types, senescent VSMCs have impaired proliferative potential coupled with increased propensity for expression of cellular senescence markers and cell death.

VSMCs aging is characterized by a shift from a contractile phenotype to a synthetic phenotype, impaired response to contractile or diastolic mediators secreted by endothelial cells, and changes in ion channel expression and abundance in the cell membrane. In atherosclerosis, senescent VSMCs may be present only in the intima rather than the mesenchyme, and VSMCs senescence is associated primarily with plaque size rather than plaque formation. Advanced atherosclerotic plaques are covered by fibrous caps containing VSMCs and extracellular matrix (ECM) molecules. Given that VSMCs can secrete and deposit ECM proteins, they are generally considered to be protective against atherosclerotic plaque instability. However, senescent VSMCs promote plaque vulnerability by secreting matrix-degrading proteases. Compared with normal VSMCs, collagen secretion from senescent VSMCs is reduced which further impairs plaque stability. Thus, senescent VSMCs not only accumulate in the atherosclerotic setting, but their properties exacerbate the development of atherosclerosis and increase the risk of atherosclerosis-related complications.

It is unclear whether senolytic drugs prevent atherosclerosis through multiple mechanisms or whether they do so only by clearing senescent cells. Not all anti-aging drugs are effective against atherosclerosis; long-term oral administration of dasatinib + quercetin (D + Q) significantly reduced aortic medial senescent cell markers in chronic hypercholesterolemic mice and naturally aging mice, as well as improving vasomotor function, but the mice still developed atherosclerosis. Further, the size of atherosclerotic plaques did not decrease following these treatments.

Researchers here note a sizable reduction in Alzheimer's disease risk in that part of the aged population that receives influenza vaccines. There is the usual question as to whether vaccination is a proxy for conscientiousness in health matters throughout later life, but here the focus is on biological mechanisms that might explain the effect. The most plausible to my eyes is the phenomenon of trained immunity, in which vaccination for a specific pathogen can provoke a general improvement in all functions of the innate immune system. This improvement includes reduced inflammation, and the chronic inflammation of aging is clearly important in the onset and progression of neurodegenerative conditions.

This retrospective cohort study revealed that in adults aged 65 or old without dementia, mild cognitive impairment, or encephalopathy, patients who received at least one influenza vaccine were 40% less likely than their non-vaccinated peers to develop incident Alzheimer's disease (AD) during the 4-year follow-up period. The mechanisms underlying the apparent protective effects of influenza vaccination on AD risk merit further investigation. These mechanisms - and those underlying the effects of adulthood vaccinations on all-cause dementia risk in general - can be grouped into at least three broad, non-exclusive categories: 1) influenza-specific mechanisms, including mitigation of damage secondary to influenza infection and/or epitopic similarity between influenza proteins and AD pathology; 2) non-influenza-specific training of the innate immune system; and 3) non-influenza-specific changes in adaptive immunity via lymphocyte-mediated cross-reactivity.

The apparent effect of influenza vaccination on AD risk may be secondary to influenza-specific immunity conferred by the vaccine. Central nervous system (CNS) injury during influenza infection can occur from direct viral invasion of nervous tissues or as collateral damage from the systemic immune response to peripheral infection. An association between flu infection and AD risk is supported by mouse studies demonstrating that peripheral infection of wild-type mice with non-neurotropic influenza strains induces excessive microglial activation and subsequent alteration of neuronal morphology, particularly in the hippocampus, that persists after infection resolution.

Long-term, non-influenza-specific alteration of the innate immune system presents another class of mechanisms potentially underlying influenza vaccination's apparent effect on AD risk. Several vaccines, including the influenza vaccine, are associated with non-specific protective effects via long-term reprogramming of innate immune cells, a process termed "trained immunity". Several studies have shown that the innate-related changes in peripheral cytokines associated with vaccination can directly affect microglial activity, including the efficiency of microglia in clearing amyloid-β aggregates. Another mechanism related to innate immunity that potentially underlies the association between flu vaccination and AD is alteration of the sustained low-grade systemic elevation of proinflammatory cytokines referred to as "inflammaging" that is commonly observed among older adults.

Link: https://doi.org/10.3233/JAD-220361

Researchers here report on an investigation of mechanisms by which aged human skin is improved in function when transplanted onto young immunocompromised mice. They identified VEGF-A as a factor involved in this improvement, and showed that delivering VEGF-A to human skin models can reduce signatures of aging. This is interesting, as a number of skin conditions exhibit high levels of VEGF-A, and are treated by therapies that are shown to inhibit VEGF-A in addition to other effects. Thus more work is needed here in order to understand whether or not VEGF-A based treatments are a viable path to improving aged skin function.

Human skin is ideally suited as a preclinical aging research model but is rarely used by mainstream aging research for this purpose. Yet, aging of the human body becomes nowhere sooner and more immediately visible than in skin changes and hair graying. While massive industry efforts therefore cater to the ancient human desire to halt or reverse the phenotype of aging skin, success at this frontier has remained moderate at best, and many product claims of in vivo rejuvenation of human skin are typically insufficiently substantiated. Nevertheless, the molecular mechanisms that underlie extrinsic and intrinsic skin aging in vivo are becoming increasingly understood, albeit mostly in nonhuman animal models of uncertain clinical relevance.

Previously, we had shown that grafting aged human skin to immunocompromised young mice reverts several aging-associated parameters in the epidermis of the human xenotransplants. Yet, it is unknown whether the observed skin rejuvenation effects extend beyond the epidermis, and the molecular mechanisms that underlie this striking epidermal rejuvenation phenomenon have remained elusive. Examining this accessible, experimentally pliable, and clinically relevant model for human organ rejuvenation in vivo, the present study hoped to identify druggable targets for human organ rejuvenation.

Transplanting aged human skin onto young immunocompromised mice morphologically rejuvenates the xenotransplants. This is accompanied by angiogenesis, epidermal repigmentation, and substantial improvements in key aging-associated biomarkers, including ß-galactosidase, p16ink4a, SIRT1, PGC1α, collagen 17A, and MMP1. Angiogenesis- and hypoxia-related pathways, namely, vascular endothelial growth factor A (VEGF-A) and HIF1A, are most up-regulated in rejuvenated human skin. This rejuvenation cascade, which can be prevented by VEGF-A-neutralizing antibodies, appears to be initiated by murine VEGF-A, which then up-regulates VEGF-A expression/secretion within aged human skin.

While intradermally injected VEGF-loaded nanoparticles suffice to induce a molecular rejuvenation signature in aged human skin transplanted onto old mice, VEGF-A treatment improves key aging parameters also in isolated, organ-cultured aged human skin, i.e., in the absence of functional skin vasculature, neural, or murine host inputs. This identifies VEGF-A as the first pharmacologically pliable master pathway for human organ rejuvenation in vivo and demonstrates the potential of our humanized mouse model for clinically relevant aging research.

Link: https://doi.org/10.1126/sciadv.abm6756

Conferences are a measure of the health of a field; typically the more conferences one sees, the broader the efforts and the larger the funding. Most of the best conferences relating to aging research, and the longevity industry that has emerged from that research, feature an even mix of entrepreneurs, scientists, and investors. The networking at these conferences leads to the foundation of new ventures and seed funding for young ventures. This is important in a field in which there are many, many opportunities to make progress. Networking makes the world turn; it is an essential part of the messy, human process of bringing new technology from the laboratory to the clinic.

Longevity industry and related, relevant conferences in the first half of this year were hectic and crowded close together in time, a result of the end of COVID-19 restrictions. Conference organizers tended to pack their delayed events into the March to June conference season. It has been a busy time for those of us who are obliged to attend! Now there will be a few months of pause before the conferences of interest resume in the later part of the year. Here, I'll note a few of the upcoming events that seem worth a look, or were interesting in past years.

Ending Age-Related Diseases 2022, August 11-14 2022, a Virtual Conference

We are delighted to announce the fifth Ending Age-Related Diseases conference on August 11-14, 2022! This virtual conference will bring together the leading experts in rejuvenation biotechnology and investment in order to foster scientific and business collaborations to develop rejuvenation therapies that target the root causes of aging.

ARDD 2022, August 29th to September 2nd 2022 in Copenhagen, Denmark

According to the United Nations, the proportion of people aged over 65 now outnumber children younger than 5. The enormous growth in the elderly population is posing a socioeconomic challenge to societies worldwide, and necessitates new sweeping interventions for age-associated diseases. This year we have an incredibly exciting program with global thought-leaders sharing their latest insights into aging and how we target aging process ensuring everyone lives a healthier and longer life. Welcome to the 9th Aging Research and Drug Discovery (ARDD) Meeting.

Longevity Summit Dublin, September 18-20 2022 in Dublin, Ireland

Join us for the Inaugural Longevity Summit in the capital city of Ireland. You will be experiencing a wonderful summit that includes a programme bursting with the "Who's Who" of longevity movement superstars, including George Church, Aubrey de Grey, Jim Mellon, and more. Gather with us for an informative, uplifting conference recognising and celebrating emerging research and developments across the Longevity Industry globally.

Longevity Investors Conference, September 28-30 2022 in Gstaad, Switzerland

The Longevity Investors Conference is the world's leading and most private longevity-focus investors only conference. LIC provides relevant insights into the longevity subject, expert education, investment opportunities, excellent networking opportunities and a great setting in an exclusive location. The two full days conference is bringing together the world's top longevity KOLs, institutional and private investors, wealthy private investors, family offices and funds.

Rejuvenation Startup Summit 2022, October 14-15 2022 in Berlin, Germany

The Rejuvenation Startup Summit, brought to you by the Forever Healthy Foundation, is a vibrant networking event that aims to accelerate the development of the rejuvenation biotech industry. Rejuvenation/Longevity biotech is a new, emerging field of medicine. It aims to prevent and reverse diseases of aging by addressing their common root cause, the aging process itself. Rejuvenation therapies aim to reverse or repair age-related cellular changes such as molecular waste, calcification, tissue stiffening, loss of stem cell function, genetic alterations, and impaired energy production. The Summit brings together startups, members of the longevity venture capital / investor ecosystem, and researchers interested in founding or joining a startup - all aiming to create therapies to vastly extend the healthy human lifespan.

The Longevity Forum, in Longevity Week, November 14-18 2022 in London

A step change in life expectancy, which is already underway and is being driven by both scientific and technological progress, will have vast implications for individuals, governments and society as a whole. To ensure that increases in longevity benefit all of society, a true public and private partnership is required to drive change and create solutions needed to equip us for this new reality. We actively engage with public and private sector stakeholders.

Eurosymposium on Healthy Ageing, November 24-26 2022 in Brussels, Belgium

The Eurosymposium on Healthy Ageing (EHA) is a unique biennial meeting of scientists working on the biology of ageing. The sixth EHA will happen in November (24 to 26) 2022. More information will follow!

Foresight Vision Weekend 2022, November 2022 in France and December 2022 in the US

Foresight Institute supports the beneficial development of high-impact technology to make great futures more likely. We focus on science and technology that is too early-stage or interdisciplinary for legacy institutions to support, for instance biotech to reverse aging. Save the date for Vision Weekend, Foresight Institute's annual member gathering. Collaborate across continents, disciplines, and generations towards flourishing futures. In 2022, we'll return with our favorite collaborators to our favorite venues: November 18-20 at Chateau du Fey, France, and December 02-04 at the Internet Archive in the Bay Area.

Researchers here outline a mechanisms by which the excess tau protein in the brain characteristic of Alzheimer's disease can interfere in the signaling between neurons that is necessary for cognitive function. Interestingly, they also suggest that a very similar mechanism is at play in the accumulation of α-synuclein in conditions such as Parkinson's disease. As always the question is always whether this mechanism is actually a meaningful contribution to the loss of function observed in patients. The brain is very complex, and neurodegenerative conditions are a mess of many, many seemingly harmful mechanisms. As the failure of past efforts to intervene in Alzheimer's disease indicates, not all of those mechanisms are important at any given stage of the condition.

A study has revealed how excess tau - a key protein implicated in Alzheimer's disease - impairs signaling between neurons in the brains of mice. The research began ten years ago, when researchers looked at the effect of high levels of soluble tau on signal transmission at the calyx of Held, the largest synapse in mammalian brains. Synapses are the places where two neurons make contact and communicate. When an electrical signal arrives at the end of a presynaptic neuron, chemical messengers, known as neurotransmitters, are released from membrane 'packets' called vesicles into the gap between neurons. When the neurotransmitters reach the postsynaptic neuron, they trigger a new electrical signal.

Using mice, the research team injected soluble tau into the presynaptic terminal at the calyx of Held and found that electrical signals generated in the postsynaptic neuron dramatically decreased. The scientists then fluorescently labelled tau and microtubules and saw that the injected tau caused new assembly of many microtubules in the presynaptic terminal. A second important clue was that elevated tau only decreased the transmission of high-frequency signals, while low-frequency transmission remained unchanged. High-frequency signals are typically involved in cognition and movement control. The researchers suspected that such a selective impact on high-frequency transmission might be due to a block on vesicle recycling. Vesicle recycling is a vital process for the release of neurotransmitters across the synapse since synaptic vesicles must fuse with the presynaptic terminal membrane, in a process called exocytosis. These vesicles are then reformed by endocytosis and refilled with neurotransmitter to be reused. If any of the steps in vesicle recycling are blocked, it quickly weakens high-frequency signals, which require the exocytosis of many vesicles.

While searching for a link between microtubules and endocytosis, the team realized that dynamin, a large protein that cuts off vesicles from the surface membrane at the final step of endocytosis, was actually discovered as a protein that binds to microtubules, although little is known about the binding site. When the scientists fluorescently labelled tau, microtubules, and dynamin, they found that presynaptic terminals that had been injected with tau showed an increase of bound dynamin, preventing the protein from carrying out its role in endocytosis. Finally, the team created many peptides with matching sequences of amino acids to parts of the dynamin protein, to see if any of them could prevent dynamin from binding to the microtubules, and therefore rescue the signaling defects caused by tau protein. When one of these peptides, called PHDP5, was injected along with tau, endocytosis and synaptic transmission remained close to a normal level.

Link: https://www.oist.jp/news-center/press-releases/untangling-role-tau-alzheimer%E2%80%99s-disease

As scientists note here, a number of reptilian and amphibian species exhibit negligible senescence, in that their mortality risk does not increase with age, at least not until very late life. The question has always been whether there is anything that can be learned from the cellular biochemistry of these species that can serve as the basis for enhancement therapies in mammals. There is no assurance that the basis of negligible senescence in any given species is simple enough to be useful. There is no assurance that even a simple difference could be safely ported over into mammalian biology given the biotechnology of the next few decades. Nonetheless, it is a topic of interest in the research community, a way to broaden the understanding of how differences in genetics and metabolism give rise to sizable differences in shape and length of life between species.

Researchers have documented that turtles, crocodilians, and salamanders have particularly low aging rates and extended lifespans for their sizes. The team also found that protective phenotypes, such as the hard shells of most turtle species, contribute to slower aging, and in some cases even "negligible aging" - or lack of biological aging. In their study, the researchers applied comparative phylogenetic methods, which enable investigation of organisms' evolution, to mark-recapture data in which animals are captured, tagged, released back into the wild and observed. Their goal was to analyze variation in ectotherm aging and longevity in the wild compared to endotherms (warm-blooded animals) and explore previous hypotheses related to aging, including mode of body temperature regulation and presence or absence of protective physical traits.

The thermoregulatory mode hypothesis suggests that ectotherms, because they require external temperatures to regulate their body temperatures and, therefore, often have lower metabolisms, age more slowly than endotherms, which internally generate their own heat and have higher metabolisms. The findings, however, reveal that ectotherms' aging rates and lifespans range both well above and below the known aging rates for similar-sized endotherms, suggesting that the way an animal regulates its temperature - cold-blooded versus warm-blooded - is not necessarily indicative of its aging rate or lifespan. The protective phenotypes hypothesis suggests that animals with physical or chemical traits that confer protection, such as armor, spines, shells or venom, have slower aging and greater longevity. The team documented that these protective traits do, indeed, enable animals to age more slowly and, in the case of physical protection, live much longer for their size than those without protective phenotypes.

Interestingly, the team observed negligible aging in at least one species in each of the ectotherm groups, including in frogs and toads, crocodilians and turtles. "It sounds dramatic to say that they don't age at all, but basically their likelihood of dying does not change with age once they're past reproduction. Negligible aging means that if an animal's chance of dying in a year is 1% at age 10, if it is alive at 100 years, it's chance of dying is still 1%. By contrast, in adult females in the US, the risk of dying in a year is about 1 in 2,500 at age 10 and 1 in 24 at age 80. When a species exhibits negligible senescence, aging just doesn't happen. Understanding the comparative landscape of aging across animals can reveal flexible traits that may prove worthy targets for biomedical study related to human aging."

Link: https://www.psu.edu/news/story/secrets-reptile-and-amphibian-aging-revealed