Fight Aging!

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Contents

• Innate Immune Activation as a Contributing Cause of Inflammaging, Reduced by Calorie Restriction
• The Contribution of Retroviral Transposable Elements to Aging
• Too Many Epigenetic Clocks, Not Enough Understanding of the Determinants of Epigenetic Age
• α-Synuclein Autoantibodies in Age-Related Neuroinflammation
• Towards the Use of Fecal Microbiota Transplantation to Rejuvenate the Gut Microbiome
• The Influence of the Gut Microbiome on the Aging of the Vasculature
• Cancer Survivors Exhibit a Significantly Higher Risk of Cardiovascular Disease
• ALCAT1 in Age-Related Mitochondrial Dysfunction
• A Longer Road for Xenotransplantation of Pig Hearts into Humans
• An Aged Gut Microbiome Impairs Hippocampal Function via the Vagus Nerve
• Lento Bio Aims to Reverse Tissue Stiffening in the Lens of the Eye
• Reporting on the Systems Aging Gordon Research Conference
• In Search of More Ways to Destroy Senescent Cells by Unleashing p53
• Oxidative Damage of Telomeres Induces Cellular Senescence
• Cellular Senescence Drives Chronic Obstructive Pulmonary Disease

Innate Immune Activation as a Contributing Cause of Inflammaging, Reduced by Calorie Restriction
https://www.fightaging.org/archives/2022/07/innate-immune-activation-as-a-contributing-cause-of-inflammaging-reduced-by-calorie-restriction/

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 Contribution of Retroviral Transposable Elements to Aging
https://www.fightaging.org/archives/2022/07/the-contribution-of-retroviral-transposable-elements-to-aging/

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.

Too Many Epigenetic Clocks, Not Enough Understanding of the Determinants of Epigenetic Age
https://www.fightaging.org/archives/2022/07/too-many-epigenetic-clocks-not-enough-understanding-of-the-determinants-of-epigenetic-age/

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.

α-Synuclein Autoantibodies in Age-Related Neuroinflammation
https://www.fightaging.org/archives/2022/07/%ce%b1-synuclein-autoantibodies-in-age-related-neuroinflammation/

Just a few of the thousands of proteins in the human body can become altered and misfold in ways that encourage other molecules of that protein to do the same, forming aggregates that precipitate into toxic, solid deposits in cells and tissue. Neurodegenerative conditions in particular are characterized by these proteins, such as amyloid-β, TDP-43, tau, and α-synuclein, the last of which is the subject of today's open access paper. Parkinson's disease is the most studied of synucleinopathies, in which an excessive buildup of α-synuclein correlates with pathology and loss of function in the brain.

The common neurodegenerative conditions are associated with chronic, unresolved inflammation in brain tissue, and there is good reason to believe that this inflammation, disruptive of cell and tissue function, is an important part of the onset and progression of neurodegeneration. To what degree are the protein aggregates found in every aged brain, and in excessive amounts in patients with neurodegenerative conditions, involved in creating that inflammation? Are their contributions sizable in comparison to, say, the presence of persistent pathogens such as herpesviruses, or the growing burden of senescent supporting cells in the brain?

The Role of Alpha-Synuclein Autoantibodies in the Induction of Brain Inflammation and Neurodegeneration in Aged Humans

Aging is a major risk factor for developing neuroinflammation. As it progresses, neuroinflammation can cause neuron death in the brain, particularly in the hippocampus. This brain region is crucial for learning and memory function. Hence, aged humans who experience loss of neurons in this region exhibit frequent tendency of memory loss. Aging and its association for the development of numerous brain diseases are continuously increasing in prevalence. Increased plasma, cerebrospinal fluid (CSF), and brain level of alpha-synuclein (α-syn) and their association to microglial cells activation, pro-inflammatory cytokines production, neurodegeneration, and cognitive deficits have been observed in aged humans. However, the exact mechanism by which such α-syn abnormalities trigger neuroinflammation in aged humans are poorly defined.

Studies have shown that irregular accumulations and distributions of α-syn and/or the development of α-syn-reactive immunoglobulin G (IgG) autoantibodies are linked to the brain production of pro-inflammatory cytokines, i.e., interleukin-1 beta (IL1β), IL-6, and tumor necrosis factor alpha (TNF-α), which lead to neuron death and memory deficits in several age-related neurodegenerative diseases, i.e., Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), rapid eye movement sleep behavior disorder (RBD), frontotemporal lobar dementia (PLD), and dementia with Lewy bodies (LBD). Therefore, this current study explored the involvement of α-syn, α-syn-reactive IgG autoantibodies, and Fc gamma receptors (FcγRs) function in aging human nervous system.

Based on the elevated brain expression of α-syn-reactive IgG auto antibodies and the higher expression of activating FcγR in aged humans, this report suggests that the α-syn-reactive IgG auto antibodies and their immunological reaction to α-syn are the basis of the formation of alpha-synuclein-specific IgG immune complexes (α-syn-IgG-ICs) in aged human brains. Furthermore, the strong interaction between such α-syn-IgG-ICs and activation of FcγR fuels the downstream signaling that causes microglial cells and/or neurons activation, pro-inflammatory cytokines production, and the death of neurons in aged humans.

Towards the Use of Fecal Microbiota Transplantation to Rejuvenate the Gut Microbiome
https://www.fightaging.org/archives/2022/07/towards-the-use-of-fecal-microbiota-transplantation-to-rejuvenate-the-gut-microbiome/

Detrimental changes in the gut microbiome might prove to be one of the easier issues to fix in the aging human body. When we talk about an aged gut microbiome, we mean that the balance of microbial populations has shifted. There are more harmful microbes that either produce damaging metabolites or otherwise engage with tissue and the immune system to provoke chronic inflammation. At the same time there are fewer beneficial microbes working to produce metabolites that are necessary for tissue function, such as the butyrate that promotes neurogenesis. Rejuvenation in the context of the gut microbiome means only rebalancing these populations, nothing more complicated than that is needed.

How to go about achieving the goal of putting a youthful microbiome into an old body? The approach with the most robust evidence in animal studies is fecal microbiota transplantation, which is to say literally taking the microbiome from a young individual and placing it into an old individual. This restores a youthful microbiome for a lasting period of time, reduces inflammation, improves other measures of health, and in short-lived species acts to extend life span. Fecal microbiota transplantation is already practiced in human medicine, but only as a treatment for C. difficle infection, in which a pathogenic microbial species has overtaken the gut, but can be out-competed by transplanted species. It would not be a great leap to adapt this to the treatment of aging.

The authors of today's open access paper are much in favor of stool banking as a way to establish material for transplantation, sampling a young individual's microbiome and storing it for later. This seems to me to have the same issues as stem cell banking, in that over a time span of decades it is highly unlikely that technology will remain static. Producing a youthful microbiome for transplant, either by screening out unwanted species from young donors, or by manufacturing to order, should be an everyday occurrence not so very long from now. Screening donors could be implemented now, given a sufficiently motivated industry.

Rejuvenating the human gut microbiome

Industrial advances have been associated with large-scale changes in the human gut microbiome and a higher incidence of complex human diseases. Rewilding the human gut microbiome by transplanting the whole gut microbial community from donors in nonindustrial societies may result in a dramatic mismatch between our industrial environment/lifestyles and the ancestral microbiome.

Emerging studies suggest that stool banking and autologous fecal microbiota transplantation (FMT), using the recipients' own stool samples collected at a younger age when they are disease-free, may be a better - or at least an alternative - solution. This leads to the idea of rejuvenating the human gut microbiome. The conceptual similarity between stool banking for autologous FMT and cord blood banking for an autologous transplant implies the potential for rejuvenating the human gut microbiome.

Here we propose rejuvenating the human gut microbiome by stool banking and autologous fecal microbiota transplantation, that is, collecting the hosts' stool samples at a younger age when they are at optimal health, and cryopreserving the samples in a stool bank for the hosts' own future use. In this article we discuss the motivation, applications, feasibility, and challenges of this solution. Basic research in cataloging, characterizing, and even engineering individual microbes (or well-defined consortia of them) and their functions (or metabolic fuels/products) is still a very promising solution to restoring a healthy gut microbiota. However, considering the daunting complexity of the human gut microbiota, both bottom-up mechanistic approaches and top-down systems approaches (based on FMT) will be needed.

The Influence of the Gut Microbiome on the Aging of the Vasculature
https://www.fightaging.org/archives/2022/07/the-influence-of-the-gut-microbiome-on-the-aging-of-the-vasculature/

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.

Cancer Survivors Exhibit a Significantly Higher Risk of Cardiovascular Disease
https://www.fightaging.org/archives/2022/07/cancer-survivors-exhibit-a-significantly-higher-risk-of-cardiovascular-disease/

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.

ALCAT1 in Age-Related Mitochondrial Dysfunction
https://www.fightaging.org/archives/2022/07/alcat1-in-age-related-mitochondrial-dysfunction/

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.

A Longer Road for Xenotransplantation of Pig Hearts into Humans
https://www.fightaging.org/archives/2022/07/a-longer-road-for-xenotransplantation-of-pig-hearts-into-humans/

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.

An Aged Gut Microbiome Impairs Hippocampal Function via the Vagus Nerve
https://www.fightaging.org/archives/2022/07/an-aged-gut-microbiome-impairs-hippocampal-function-via-the-vagus-nerve/

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.

Lento Bio Aims to Reverse Tissue Stiffening in the Lens of the Eye
https://www.fightaging.org/archives/2022/07/lento-bio-aims-to-reverse-tissue-stiffening-in-the-lens-of-the-eye/

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 that include 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."

Reporting on the Systems Aging Gordon Research Conference
https://www.fightaging.org/archives/2022/07/reporting-on-the-systems-aging-gordon-research-conference/

Alex Zhavoronkov, who these days is as much interested in accelerating progress in cryonics as in translational research for the treatment of aging, here reports on his time at the recent Systems Aging Gordon Research Conference, one of a growing number of new conference series serving academic efforts make headway in the matter of treating aging as a medical condition. As a general rule, more successful conference series tend to indicate a larger and more successful field: more researchers, more funding, more attention from the world at large. The proliferation of conferences focused on aging is a good sign.

With Vadim Gladyshev serving as chairman and Steve Horvath as vice-chairman, the conference set the stage for the field, paving the way for the development of interventions to delay and reverse aging. Both are world-renowned researchers, and spoke and led the discussions at the conference. The conference was attended by a number of prominent researchers from renowned institutions; such as Cynthia Kenyon of Calico Labs, who discussed about interventions that slow aging, Morten Scheibye-Knudsen of the University of Copenhagen, who talked about modulating DNA repair for healthy aging, and Emma Teeling of the University College Dublin, who spoke about the genetic basis of exceptional longevity of bats.

Day one was about "Delaying Age," and was led by Steve Horvath as the discussion leader. On this day, Cynthia Kenyon, Richard Miller of the University of Michigan and Inigo Martincorena of the Sanger Institute presented. Richard and Inigo presented on drugs and mutations that slow aging in mice, and somatic mutations and clonal expansions in aging, respectively. Day two was all about "Epigenetic Reprogramming and Rejuvenation." It was led by Joe Betts-LaCroix of Retro Biosciences. Manuel Serrano of IRB Barcelona started the day with a talk on understanding and manipulating in vivo reprogramming and its effects on aging. He was followed by Vittorio Sebastiano of Stanford University, who spoke about transient reprogramming for multifaceted reversal of aging. Jacob Kimmel of NewLimit Research followed Vittorio with a talk on reprogramming strategies to restore youthful gene expression. Then came Morgan Levine of Yale University, who discussed DNA methylation landscapes in aging and reprogramming.

The first discussion topic for day three was "Epigenetic Biomarkers," with Kristen Fortney of Bioage leading the discussions. First to the podium was Nick Schaum of Astera Institute, whose discussion topic was "rejuvenome: toward a functional and multiomics understanding of aging and rejuvenation". He was followed by Riccardo Marioni of University of Edinburgh and Ake Lu of San Diego Institute of Science, who discussed about epigenetic clocks and universal DNA methylating age, respectively. "Artificial Intelligence and Machine Learning" was the first subject matter for day four, which was moderated by Marc Kirschner of Harvard. Sergiy Libert of Calico started the day with a talk on construction and analysis of the physiology clock for human aging. I took to the podium next and discussed applications of deep aging clocks in clinical practice and drug discovery. I was followed by Kristen Fortney of Bioage and Albert-laszlo Barabasi of Northeastern University, who discussed data-informed drug discovery for aging and the dark matter of nutrition, respectively.

Over the course of the five-day event, presentations covered many topics, like delaying aging, aging clocks, longevity intervention, and so much more. Many organizations like MIT, Stanford, and Yale were represented. It was truly a great opportunity to network with peers. With this successful conference on aging, the GRC has now plans the second Systems Aging meeting in 2024.

In Search of More Ways to Destroy Senescent Cells by Unleashing p53
https://www.fightaging.org/archives/2022/07/in-search-of-more-ways-to-destroy-senescent-cells-by-unleashing-p53/

Based on animal data, the growing burden of senescent cells with age appears to provide a significant contribution to age-related degeneration. Cells become senescent in response to tissue injury, significant cellular damage, signaling from other senescent cells, or reaching the Hayflick limit on replication. In youth, senescent cells are efficiently cleared, either destroying themselves via programmed cell death, or being destroyed by the immune system. In later life, clearance slows, and as a result there are ever more lingering senescent cells delivering signals that disrupt tissue structure and function and provoking chronic inflammation. Removing these cells via senolytic therapies has been shown to produce rapid reversal of many age-related pathologies in mice, and thus the research community is actively engaged in finding more ways to selectively provoke programmed cell death in senescent cells, to add to those already discovered.

Super-enhancers regulate genes with important functions in processes that are cell type-specific or define cell identity. Mouse embryonic fibroblasts establish 40 senescence-associated super-enhancers regardless of how they become senescent, with 50 activated genes located in the vicinity of these enhancers. Here we show, through gene knockdown and analysis of three core biological properties of senescent cells that a relatively large number of senescence-associated super-enhancer-regulated genes promote survival of senescent mouse embryonic fibroblasts.

Of these, Mdm2, Rnase4, and Ang act by suppressing p53-mediated apoptosis through various mechanisms that are also engaged in response to DNA damage. MDM2 and RNASE4 transcription is also elevated in human senescent fibroblasts to restrain p53 and promote survival. These findings further support the idea that senescent cells actively combat apoptosis on multiple fronts and therefore have numerous therapeutically exploitable vulnerabilities for elimination of detrimental senescent cells implicated in aging and aging-related diseases. These insights provide molecular entry points for the development of targeted therapeutics that eliminate senescent cells at sites of pathology.

Oxidative Damage of Telomeres Induces Cellular Senescence
https://www.fightaging.org/archives/2022/07/oxidative-damage-of-telomeres-induces-cellular-senescence/

The accumulation of senescent cells is a contributing cause of degenerative aging. Researchers are very interested in better understanding the processes by which cells are pushed into the senescent state, as this knowledge might lead to better approaches to prevention of senescence. It remains an open question as to the degree to which prevention of senescence via any specific mechanism is beneficial versus harmful. Will it primarily allow cells on the edge of senescence due to transient circumstances, or circumstances that otherwise have little effect on cell viability, to recover and be productive in tissues? Will it allow damaged and potentially cancerous cells to continue their activities unimpeded? These questions remain to be answered on a case by case basis.

When a healthy human cell divides to form two identical cells, a small piece of DNA is shaved off each chromosome's tip, so that telomeres become gradually shorter with each division. However, it remains unclear whether over a person's lifetime, a cell may divide so often that its telomeres erode completely, prompting transition to a senescent state. Researchers have known for decades that telomere shortening triggers senescence in lab-grown cells, but they could only hypothesize that DNA damage at telomeres could make cells senescent.

Until now, testing this hypothesis had not been possible because the tools used to damage DNA were non-specific, causing lesions across the whole chromosome. A new tool uses a special protein that binds exclusively to telomeres. This protein acts like a catcher's mitt, grabbing hold of light-sensitive dye "baseballs" that researchers tossed into the cell. When activated with light, the dye produces DNA-damaging reactive oxygen molecules. Because the dye-catching protein binds only to telomeres, the tool creates DNA lesions specifically at chromosome tips.

Using human cells grown in a dish, the researchers found that damage at telomeres sent the cells into a senescent state after just four days - much faster than the weeks or months of repeated cell divisions that it takes to induce senescence by telomere shortening in the lab. "We found a new mechanism for inducing senescent cells that is completely dependent on telomeres. These findings also solve the puzzle of why dysfunctional telomeres are not always shorter than functional ones. Now that we understand this mechanism, we can start to test interventions to prevent senescence. For example, maybe there are ways to target antioxidants to the telomeres to protect them from oxidative damage."

Cellular Senescence Drives Chronic Obstructive Pulmonary Disease
https://www.fightaging.org/archives/2022/07/cellular-senescence-drives-chronic-obstructive-pulmonary-disease/

Researchers here review the evidence for accumulating numbers of senescent cells to drive the dysfunction of chronic obstructive pulmonary disease (COPD). It is now well known that senescent cells secrete a potent mix of signals that provoke inflammation and remodeling of tissue structure. This is necessary in the short term as a response to injury, potentially cancerous cells, and similar issues that require the attention of the immune system, regeneration, and potentially the destruction of errant cells. When sustained for the long term, however, it is highly disruptive to tissue structure and function, producing outcomes such as fibrosis and a chronic, unresolved inflammation that harmfully alters cell behavior.

Researchers coined the term "COPD-associated secretory phenotype" (CASP) to refer to the inflammatory mediators that are increased in COPD and provided a comparison of CASP and senescence-associated secretory phenotype (SASP) factors. In summary, there is a large degree of overlap, supporting the notion that they are strongly linked and reinforces the theory that senescence, along with SASP, is a major contributor to the inflammation that defines COPD.

Typically, cells undergoing senescence chemoattract immune cells, resulting in clearance of these senescent cells by immune cells such as NK cells and macrophages. However, senescent cells in diseased tissues can also impede innate and adaptive immune responses. Senescent cells accumulate in tissues during aging and could influence several pathological features observed in COPD, such as inflammation-associated tissue damage and remodeling. It is difficult to determine whether inflammation observed in COPD is primarily due to senescence, as many other contributing factors within the disease may contribute. However, the presence of enhanced senescent cell frequency in the lungs does contribute to a modified immune response that may influence several aspects of COPD pathogenesis.

There is increasing interest in the resolution of abundant senescence as a potential therapeutic approach in COPD. Senolytic agents, compounds that facilitate the elimination of senescent cells, have received considerable attention lately as a potential treatment for COPD. However, the investigation of these agents is limited by the lack of universal markers of senescence. A better understanding of pathways that induce and reinforce senescence in COPD may allow us to discover possible biomarkers that could serve as targets for these senolytic therapies.

Overall, there is mounting evidence to suggest that senescence could contribute to cells being resistant to apoptosis, exhibiting elevated inflammation, and reduced dead cell clearance, resulting in extensive tissue remodeling observed in COPD. Targeting senescent cells using senolytics to selectively remove senescent cells or modulate SASP using small molecules or antibodies represents a novel approach to countering COPD progression. Several treatments that may target cellular senescence are in development.