July 16th, 2023

Fight Aging! Newsletter, July 17th 2023

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

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Contents

Potentially Interesting Longevity-Related Conferences for the Remainder of 2023
https://www.fightaging.org/archives/2023/07/potentially-interesting-longevity-related-conferences-for-the-remainder-of-2023/

A number of organizations organize yearly conferences relevant to both participants in the longevity industry and its surrounding community, and those who want to participate, whether as investors, researchers, advocates, entrepreneurs, or employees of biotech startups. Here I'll point out a few events that may be of interest to those who want to become more involved in this field. Come out to attend some of the better conferences! That is is the advice I give to most people who want to work in a longevity biotech company, start a longevity biotech company, make connections with self-experimenters and those who know more about the current state of research, or simply learn more about who is who. For another list of industry conferences, one might look to the Aging Biotech Info conference page.

August 10th, 2023: Ending Age-Related Diseases, New York City

Lifespan.io has organized a yearly conference series in NYC for some time now. This year they are trying something new, and mixing the longevity community with the blockchain community. A good number of high net worth blockchain industry folk have a strong interest in the longevity industry, and have both invested in biotech companies and funded research programs. There are also initiatives like VitaDAO that emerged from an intersection of the interest in longevity and blockchain applications, this being one of the more interesting attempts of the past twenty years to try to create a sustainable financial incentive to fund early stage research.

August 17th, 2023: Longevity Summit Dublin 2023, Dublin

The LEV Foundation, the present vehicle for the work of Aubrey de Grey since his separation from the SENS Research Foundation, hosts a yearly event in Dublin, Ireland. Like the conferences hosted by the SENS Research Foundation and Forever Healthy Foundation in past years, the summit aims to be a good mix of pushing forward on the fundamental science of rejuvenation, as well as bringing that science into the clinic.

August 28th, 2023: the 10th Aging Research and Drug Discovery Meeting, Copenhagen

ARDD is a primarily scientific conference focused on research that might lead to treatments for aging, but the event also attracts a significant number of of longevity industry entrepreneurs and investors. For industry participants, this is the mixture to seek out, as it offers the greatest chance of fortunate connections. Perhaps by virtue of continuing largely undaunted while other conferences were slow to return following COVID-19, ARDD has become one of largest and best events for that part of the longevity community that lies at the intersection of industry and academia.

September 7th, 2023: RAAD Festival, Anaheim

RAADfest remains, as in past years, a fascinating mix of scientists and alchemists, legitimate companies working on means of rejuvenation next to the frauds of the "anti-aging" industry. Go, by all means, should you feel equipped to tell the difference! At some point, working medicine that is capable of achieving a specific goal in control over the human body drives out the charms and potions. It hasn't happened yet in the matter of aging, but it will as the longevity industry advances.

September 27th, 2023: Longevity Investors Conference, Gstaad

As the title might suggest, this is a fully investor-focused conference intended to directly educate and expand the investor community focused on the longevity industry. While that investor community has certainly expanded by leaps and bounds in recent years, many more participants are needed as increasing numbers of longevity industry companies move beyond the preclinical stage of development into the very much more expensive clinical stage. The sizable funding for clinical trials of therapies capable of slowing or reversing the mechanisms of aging must come from somewhere, and educating the community of conservative investors that manage very large funds is a project in and of itself.

December 1st, 2023: Foresight Vision Weekend, Paris and San Francisco

The Foresight Institute puts on a number of events relevant to the longevity community, firstly a longevity-focused workshop earlier in the year and then a yearly gathering that covers all of the organization's areas of interest in developing technologies, including the treatment of aging as a medical condition. The crowd is typically made up of the Bay Area investment and entrepreneurial community, but it draws visitors from many parts of the longevity industry and research community. It is an excellent opportunity to make connections with people who have been at the core of the longevity industry since its inception.

December 5th, 2023: Longevity Summit, San Francisco

The Longevity Summit is a new conference series, held at the Buck Institute just north of the Bay Area. Like the other conferences I'd consider to be at the better end of the spectrum, the organizers make an effort to gather together a good mix of scientists, entrepreneurs, and investors. I didn't attend last year, but those who did spoke highly of it.

December 7th, 2023: 23rd Bay Area Aging Meeting, San Francisco

While ostensibly a meeting for the scientific community, plenty of the participating labs have given rise to longevity industry biotech companies in recent years. Still, this is probably the most wholly academic/scientific of the events in this list. If you are a scientist at an academic institution in the US, starting here might be a good plan.

The Influence of Chronic Inflammation on the Hallmarks of Aging
https://www.fightaging.org/archives/2023/07/the-influence-of-chronic-inflammation-on-the-hallmarks-of-aging/

Chronic inflammation is a feature of aging, a continual activation of the immune response without any triggering injury or infection. Many different mechanisms contribute to this state of unresolved inflammatory signaling: the accumulation of senescent cells and the senescence-associated secretory phenotype (SASP); mitochondrial dysfunction leading to mislocalized mitochondrial DNA that triggers an innate immune reaction; signaling from visceral fat cells in those who are overweight; changes in the gut microbiome and intestinal barrier that allow microbes and microbial metabolites to provoke the immune system; and so on and so forth.

Inflammatory signaling is vital in the short term, necessary for the immune response to function correctly in the context of regeneration from injury, destruction of pathogens, and destruction of malfunctioning cells. When sustained for the long term, however, inflammatory signaling becomes increasingly disruptive to cell and tissue function. A meaningful fraction of degenerative aging results from chronic inflammation; research suggests that all of the common fatal age-related conditions have a strong inflammatory component to their pathologies.

Chronic inflammation and the hallmarks of aging

Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation during aging, without overt infection, is defined as "inflammaging," which is associated with increased morbidity and mortality in the aging population. Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions, such as cardiovascular diseases, neurodegeneration, cancer, and frailty. How the crosstalk between chronic inflammation and other hallmarks of aging underlies biological mechanisms of aging and age-related disease is thus of particular interest to the current geroscience research.

This review integrates the cellular and molecular mechanisms of age-associated chronic inflammation with the other eleven hallmarks of aging. Extra discussion is dedicated to the hallmark of "altered nutrient sensing". The deregulation of hallmark processes during aging disrupts the delicate balance between pro-inflammatory and anti-inflammatory signaling, leading to a persistent inflammatory state. The resultant chronic inflammation, in turn, further aggravates the dysfunction of each hallmark, thereby driving the progression of aging and age-related diseases.

The crosstalk between chronic inflammation and other hallmarks of aging results in a vicious cycle that exacerbates the decline in cellular functions and promotes aging. Understanding this complex interplay will provide new insights into the mechanisms of aging and the development of potential anti-aging interventions. Given their interconnectedness and ability to accentuate the primary elements of aging, drivers of chronic inflammation may be an ideal target with high translational potential to address the pathological conditions associated with aging.

Recombinant Klotho Treatment Improves Cognitive Function in Old Rhesus Macaques
https://www.fightaging.org/archives/2023/07/recombinant-klotho-treatment-improves-cognitive-function-in-old-rhesus-macaques/

Klotho is one of the few genuinely longevity-associated genes, in that greater than normal expression increases life span in mice, while lower than normal expression shortens life span in mice. In humans, greater levels of circulating soluble klotho correlate with greater longevity. Klotho is thought to operate in the kidneys, in some way that is protective against the mechanisms of age-related decline, but there is a great deal of evidence for greater circulating klotho to improve cognitive function. At the same time, it seems unclear as to whether klotho is actually doing anything in the brain; it may be that the benefit is derived from preventing loss of kidney function, as kidney function is quite important to brain health. Still, this is subject to further discovery, and far from being a settled answer.

Various groups are working towards the use of the recombinant klotho protein as a therapy, or some form of gene therapy as a way to increase circulating levels in humans. This seems as likely to be initially developed as a treatment for cognitive impairment as for kidney conditions, given the evidence on the table. Certainly, that is the intent at UNITY Biotechnology, a company that licensed academic work from recent years on the effects of soluble klotho on cognitive function in mice. That same line of work now leads to today's study, in which soluble klotho is tested as a protein therapy in aged non-human primates. It appears to work as a way to improve cognitive function, but interestingly only at lower doses, suggesting that the path forward is probably going to be more complex than desired.

Longevity factor klotho enhances cognition in aged nonhuman primates

Klotho (KL) is a longevity factor that declines in aging. Elevating KL boosts cognitive functions in mice through transgenic overexpression and acute peripheral administration. KL (secreted α-klotho) circulates as a hormone following cleavage from its transmembrane form and impacts insulin and fibroblastic growth factor (FGF) signaling, Wnt and N-methyl-d-aspartate receptor (NMDAR) functions. Systemic elevation of KL in mice increases synaptic plasticity, cognition, and neural resilience to aging, Alzheimer's, and Parkinson's disease-related toxicities. Notably, systemic administration of KL does not cross the blood-brain barrier. Human relevance for KL in brain health is supported by studies showing that individuals with elevated KL, due to genetic Klotho variation or other reasons, demonstrate better cognition, attenuated neuropathological measures, or decreased dementia risk in aging and Alzheimer's disease.

We sought to test whether a low-dose, subcutaneous administration of KL could, in parallel to mice, boost cognition in aged rhesus macaques, a type of non-human primate (NHP). Like humans, rhesus macaques undergo age-induced cognitive decline with synaptic changes, without significant neuronal loss, impairing brain regions, including the hippocampus and prefrontal cortex (PFC). Targeted earlier by aging, the PFC subserves executive functions such as working memory and, in rhesus macaques, shows age-induced deficits in neuronal firing, regulated protein kinase C (PKC) activity, neurotransmitter balance and structural decline.

Our primary goal was to test whether a KL dose in rhesus macaques that increases serum levels to a range present during the human lifespan, and is comparable to therapeutically effective increases in mice, can enhance cognition. Our secondary goal was to explore higher KL doses in rhesus macaques to test whether KL-mediated benefits on cognition could be dose-dependent. Our data show that KL (10 μg/kg) enhanced cognition in aging rhesus macaques, an effect that persisted for at least 2 weeks in measures of memory. KL-mediated cognitive enhancement similarly persisted in mice for at least 2 weeks, suggesting organizational, longer-lasting and beneficial effects on the synapse and brain. In both species, the cognitive effect outlasted the putative half-life of the hormone, 7 minutes in rodents and estimated at 29.5 hours in aging rhesus macaques.

Higher doses of KL (20 and 30 μg/kg) did not enhance cognition in monkeys. Of note, the higher doses tested did not impair cognition as the 2-5% changes were not significantly increased or decreased statistically; however, it remains to be determined whether doses even higher than those tested could impair cognition. Together, these data indicate that KL-mediated cognitive enhancement extends to NHPs in a complex genetic, anatomical, and functional brain similar to humans. These data also suggest that lower, more 'physiological' levels of the hormone in the body may be required for a therapeutic window of cognitive enhancement in humans.

Resibufogenin as a Senolytic Compound
https://www.fightaging.org/archives/2023/07/resibufogenin-as-a-senolytic-compound/

Researchers continue to search for novel senolytic compounds, those capable of selectively destroying senescent cells while producing a minimal impact on other cells. In youth, senescent cells are rapidly cleared by the immune system, but this clearance falters with age, leading to an accumulating burden of senescence in tissues throughout the body. These lingering senescent cells secrete pro-growth, pro-inflammatory signals that are disruptive to tissue structure and function when sustained over the long term. The lasting presence of senescent cells contributes to the chronic inflammation of aging, as well as to the onset and progression of near all age-related conditions. Animal studies show that clearance of these errant cells can reverse a broad range of age-related conditions, and thus there is considerable interest in the development of senolytic drugs to achieve the same result in humans.

Today's open access paper is illustrative of many similar efforts to discover usefully senolytic compounds that may already exist the vast databases of widely used medicinal products. New discoveries might form the basis for a later clinical development program. Given that every older adult is a potential customer for senolytic drugs, and that these drugs are expected to vary widely in their efficacy from tissue to tissue, there is more than enough room for many different senolytics-focused companies to coexist, and more than enough room for success in many different senolytic clinical programs. We should expect to see a considerable expansion of the set of known senolytic compounds and mechanisms for senolysis in the years ahead.

Identification of resibufogenin, a component of toad venom, as a novel senolytic compound in vitro and for potential skin rejuvenation in male mice

Senescent cells that accumulate with age have been shown to contribute to age-related diseases and organ dysfunction and have attracted attention as a target for anti-aging therapy. In particular, the use of senescent cell-depleting agents, or senolytics, has been shown to improve the aging phenotype in animal models. Since senescence has been implicated in the skin, particularly in fibroblasts, this study used aged human skin fibroblasts to investigate the effects of resibufogenin.

A component of the traditional Chinese medicine toad venom, resibufogenin was investigated for senolytic and/or senomorphic activity. We found that the compound selectively caused senescent cell death without affecting proliferating cells, with a marked effect on the suppression of the senescence-associated secretory phenotype. We also found that resibufogenin causes senescent cell death by inducing a caspase-3-mediated apoptotic program. Administration of resibufogenin to aging mice resulted in an increase in dermal collagen density and subcutaneous fat, improving the phenotype of aging skin. In other words, resibufogenin ameliorates skin aging through selective induction of senescent cell apoptosis without affecting non-aged cells. This traditional compound may have potential therapeutic benefits in skin aging characterized by senescent cell accumulation.

Late Life Rapamycin Treatment Reverses Diastolic Dysfunction in Mice
https://www.fightaging.org/archives/2023/07/late-life-rapamycin-treatment-reverses-diastolic-dysfunction-in-mice/

Inhibitors of mTOR such as rapamycin are increasingly well studied. This class of drug stimulates cellular stress responses, principally autophagy, and thus produces outcomes that are broadly similar to the long-term improvement of health resulting from calorie restriction, exercise, or other demonstrated means of upregulating autophagy. This results in benefits to health, such as those noted in today's open access paper.

It is one thing to demonstrate that a drug improves measures of autophagy known to decline with age, and note that many of the interventions shown to modestly slow aging in laboratory species are characterized by improved autophagy. It is quite another to determine the links between low-level change in cell biochemistry and high level tissue properties. Cellular metabolism is enormously complex, and comparatively little headway has been made towards building broad bridges between (a) specific causative mechanisms of aging, (b) downstream issues with cellular biochemistry such as faltering autophagy, and (c) mechanical, structural, and other properties of tissue and organ function. It remains the case that knowing that a particular intervention works to improve health does not imply knowing how it works to improve health in detail.

Late-life Rapamycin Treatment Enhances Cardiomyocyte Relaxation Kinetics and Reduces Myocardial Stiffness

Diastolic function is controlled by active relaxation of cardiomyocytes and passive stiffness of the myocardium. Cardiomyocyte relaxation is controlled by the interplay of two macromolecular systems: membrane bound Ca2+ handling proteins to send the signal to start and stop contraction, and sarcomeric proteins for force generation and contraction regulation by Ca2+. Passive stiffness of the myocardium is controlled by mechanisms such as extracellular matrix remodeling, titin isoform shift and titin phosphorylation. It has been shown that rapamycin reduces the age-related increase in passive stiffness of the myocardium. The effects of rapamycin on active cardiomyocyte relaxation and the precise molecular mechanisms of rapamycin mediated reduction in passive myocardial stiffness remain unknown. Identifying the mechanisms by which rapamycin improves diastolic function in the aging heart will advance our understanding on its therapeutic potentials in cardiac aging and heart failure with preserved ejection fraction (HFpEF).

To dissect the mechanisms by which rapamycin improves diastolic function in old mice, we examined the effects of rapamycin treatment at the levels of single cardiomyocyte, myofibril, and multicellular cardiac muscle. Compared to young cardiomyocytes, isolated cardiomyocytes from old control mice exhibited prolonged time to 90% relaxation (RT90) and time to 90% Ca2+ transient decay (DT90), indicating slower relaxation kinetics and calcium reuptake with age. Late-life rapamycin treatment for 10 weeks completely normalized RT90 and partially normalized DT90, suggesting improved Ca2+ handling contributes partially to the rapamycin-induced improved cardiomyocyte relaxation.

In addition, rapamycin treatment in old mice enhanced the kinetics of sarcomere shortening and Ca2+ transient increase in old control cardiomyocytes. Myofibrils from old rapamycin-treated mice displayed increased rate of the fast, exponential decay phase of relaxation compared to old controls. The improved myofibrillar kinetics were accompanied by an increase in MyBP-C phosphorylation following rapamycin treatment. We also showed that late-life rapamycin treatment normalized the age-related increase in passive stiffness of demembranated cardiac trabeculae through a mechanism independent of titin isoform shift. In summary, our results showed that rapamycin treatment normalizes the age-related impairments in cardiomyocyte relaxation, which works conjointly with reduced myocardial stiffness to reverse age-related diastolic dysfunction.

A Clinical Trial of Transplanted Neurons Derived From Induced Pluripotent Stem Cells
https://www.fightaging.org/archives/2023/07/a-clinical-trial-of-transplanted-neurons-derived-from-induced-pluripotent-stem-cells/

In past years, researchers have attempted various forms of cell therapy for Parkinson's disease, with the goal of replacing the population of dopamine generating neurons that are lost to disease processes. Fetal sources of neurons have been used, but since the discovery of cellular reprogramming, the trajectory has been towards the production of neurons from induced pluripotent stem cells. As noted here, this has reached the stage of human clinical trials.

Bayer AG and BlueRock Therapeutics LP, a clinical stage cell therapy company and wholly owned independently operated subsidiary of Bayer AG, today announced positive top-line results from a Phase I clinical trial of investigational drug, bemdaneprocel (BRT-DA01), a potential first-in-class cell therapy for Parkinson's disease. The trial showed that bemdaneprocel was well-tolerated in all 12 patients in the study to date, with no major safety events. In addition, an assessment of the study's secondary endpoints demonstrated feasibility of transplantation and evidence of cell survival and engraftment in the brain through one year. Based on these results, planning is underway for a Phase II study that is expected to begin enrolling patients in H1 (first half) 2024.

Bemdaneprocel (BRT-DA01), an investigational therapy comprised of dopamine producing neurons derived from pluripotent stem cells, is surgically implanted into the brain of a person with Parkinson's disease. When transplanted, these cells have the potential to reform neural networks that have been destroyed by Parkinson's disease in the hope of restoring motor and non-motor function to patients. The primary objective of the Phase I trial is to assess the safety and tolerability of bemdaneprocel (BRT-DA01) transplantation at one-year post-transplant. The secondary objectives of the trial are to assess the evidence of transplanted cell survival and motor effects at one- and two-years post-transplant, to evaluate continued safety and tolerability at two years, and to assess feasibility of transplantation.

Longevity-Associated FLT1 Variant May Protect Against Hypertension Consequences
https://www.fightaging.org/archives/2023/07/longevity-associated-flt1-variant-may-protect-against-hypertension-consequences/

The FLT1 gene encodes the vascular endothelial growth factor receptor 1 (VEGFR1) protein, relevant to the process of angiogenesis, among others. Researchers here note that a longevity-associated variant of FLT1 appears to be protective in hypertensive individuals. It is tempting to speculate as how this variant beneficially alters blood vessel maintenance and creation, but finding out would require much more than just the epidemiological data presented here.

Longevity is written into the genes. While many so-called "longevity genes" have been identified, the reason why particular genetic variants are associated with longer lifespan has proven to be elusive. The aim of the present study was to test the hypothesis that the strongest of 3 adjacent longevity-associated single nucleotide polymorphisms - rs3794396 - of the vascular endothelial growth factor receptor 1 gene, FLT1, may confer greater lifespan by protecting against mortality risk from one or more adverse medical conditions of aging - namely, hypertension, coronary heart disease (CHD), stroke, and diabetes.

In a prospective population-based longitudinal study we followed 3,471 American men of Japanese ancestry living on Oahu, Hawaii, from 1965 until death or to the end of December 2019 by which time 99% had died. Cox proportional hazards models were used to assess the association of FLT1 genotype with longevity for 4 genetic models and the medical conditions. We found that, in major allele recessive and heterozygote disadvantage models, genotype GG ameliorated the risk of mortality posed by hypertension, but not that posed by having CHD, stroke, or diabetes. Normotensive subjects lived longest and there was no significant effect of FLT1 genotype on their lifespan.

In conclusion, the longevity-associated genotype of FLT1 may confer increased lifespan by protecting against mortality risk posed by hypertension. We suggest that FLT1 expression in individuals with longevity genotype boosts vascular endothelial resilience mechanisms to counteract hypertension-related stress in vital organs and tissues.

Resistance Exercise Slows the Onset of Pathology in a Mouse Model of Alzheimer's Disease
https://www.fightaging.org/archives/2023/07/resistance-exercise-slows-the-onset-of-pathology-in-a-mouse-model-of-alzheimers-disease/

With the caveat that mouse models of Alzheimer's disease are quite artificial, as aged wild-type mice do not suffer from any condition resembling Alzheimer's, and the models are thus built upon assumptions about which processes are important to the progression of the condition, researchers here show that resistance exercise slows the pathology and loss of cognitive function in one such model. Resistance exercise is well demonstrated to improve metabolism, immune function, and reduce mortality in both older animals and humans. It would not be too surprising to find that sedentary individuals are performing more poorly in the onset of dementia in addition to other aspects of degenerative aging.

Physical exercise has beneficial effects by providing neuroprotective and anti-inflammatory responses to Alzheimer's disease (AD). Most studies, however, have been conducted with aerobic exercise, and few have investigated the effects of other modalities that also show positive effects on AD, such as resistance exercise (RE). In addition to its benefits in developing muscle strength, balance and muscular endurance favoring improvements in the quality of life of the elderly, RE reduces amyloid load and local inflammation, promotes memory and cognitive improvements, and protects the cortex and hippocampus from the degeneration that occurs in AD.

Therefore, the aim of this study was to investigate the effects of 4 weeks of RE intermittent training on the prevention and recovery from these AD-related neuropathological conditions in APP/PS1 mice. For this purpose, 6-7-month-old male APP/PS1 transgenic mice and their littermates, negative for the mutations (Control), were distributed into three groups: Control, APP/PS1, APP/PS1+RE. RE training lasted four weeks and, at the end of the program, the animals were tested in the open field test for locomotor activity and in the object recognition test for recognition memory evaluation. The brains were collected for immunohistochemical analysis of Aβ plaques and microglia, and blood was collected for plasma corticosterone by ELISA assay.

APP/PS1 transgenic sedentary mice showed increased hippocampal Aβ plaques and higher plasma corticosterone levels, as well as hyperlocomotion and reduced central crossings in the open field test, compared to APP/PS1 exercised and control animals. The intermittent program of RE was able to recover the behavioral, corticosterone and Aβ alterations to the Control levels. In addition, the RE protocol increased the number of microglial cells in the hippocampus of APP/PS1 mice. Altogether, the present results suggest that RE plays a role in alleviating AD symptoms, and highlight the beneficial effects of RE training as a complementary treatment for AD.

The Prospect of Senotherapeutics to Treat Skin Aging
https://www.fightaging.org/archives/2023/07/the-prospect-of-senotherapeutics-to-treat-skin-aging/

Will senolytic drugs to destroy senescent cells and senomorphic drugs to reduce the harmful senescence-associated secretory phenotype (SASP) turn out to improve on present poor approaches to treat skin aging in humans? Few groups appear motivated to find out. Those developing senotherapeutics as drugs focus on more serious concerns than skin aging, and are arguably right to do so, while those developing senotherapeutics as cosmetics have little incentive to conduct expensive, robust clinical trials of their products. Success in selling cosmetic products has little connection with whether or not the products actually work. Nonetheless, we might hope that at some point someone will robustly quantify the effects of clearing senescent cells on the aging of human skin.

In recent years, researchers have attempted to counteract aging using senotherapeutics that selectively target senescent cells. Senotherapeutics are categorized into two groups. Senolytic drugs selectively eliminate senescent cells, and senomorphic drugs inhibit the negative effects of their SASP. Since the combination of dasatinib and quercetin was proposed as the first senolytic drug to suppress genes that are increased in senescent cells, many studies have shown that various substances such as ABT-737, ABT-263, A1155463, and fisetin have anti-aging properties.

In particular, ABT-263 and ABT-737, which are Bcl-2 inhibitors, have been found to selectively eliminate SA β-gal-positive senescent cells in skin both in vitro and ex vivo. Researchers demonstrated that either ABT-263 or ABT-737 treatment selectively eliminated dermal fibroblasts in an intrinsic skin aging mouse model. They also showed that the treatment increased the collagen density, epidermal thickness, and keratinocyte proliferation while reducing SASPs including MMP-1 and IL-6. Further, the team revealed that treatment with ABT-263 and ABT-737 also attenuated the induction of MMPs and decreased collagen density in the photoaging mouse model. In addition, ABT-263 showed potential in reducing pigmentation caused by photoaging in human skin inducing apoptosis of p16INK4A-positive fibroblasts with its senolytic activity, resulting in decreased levels of melanin and tyrosinase activity.

One of the most notable targets of senomorphic agents is the mechanistic target of rapamycin (mTOR) pathway, which regulates cellular metabolism and is linked to cellular growth, proliferation, and autophagy. The mTOR pathway is also involved in the synthesis of SASP. Rapamycin, an mTOR inhibitor, exhibited significant reduction in senescence markers and SASP as well as oxidative stress in UV-induced photoaged human dermal fibroblasts. Moreover, researchers revealed the potential anti-aging effect of topical application of rapamycin (an mTOR inhibitor). A total of 17 subjects over the age of 40 years with age-related photoaging of the skin applied a rapamycin-containing hand cream to the dorsum of one hand and a placebo hand cream to the other hand daily for 8 months and found that the rapamycin-treated hand had a decrease in p16 and an increase in collagen VII protein.

Taken together, these promising results suggest that senotherapeutics may be a novel therapeutic option for skin aging; however, the limitations of these drugs, such as their specificity, selectivity, and efficiency, still need to be addressed, and their mechanisms of action and side effects must be better understood.

Reviewing Efforts to Use Cells and Scaffolds to Regenerate the Heart
https://www.fightaging.org/archives/2023/07/reviewing-efforts-to-use-cells-and-scaffolds-to-regenerate-the-heart/

The heart is one of the least regenerative tissues in the body. Damage resulting from loss of blood flow during a heart attack leads to scarring and loss of function, rather than any meaningful degree of regeneration. While preventing the atherosclerosis that causes occlusion of blood vessels is the most desirable goal, finding ways to repair a damaged heart is also a high priority for the research community. Many groups have worked towards regenerative therapies based on delivery of cells and scaffolding material, even layers of artificial tissue made by combining the two, but progress has been frustratingly slow.

Cardiovascular diseases (CVD) are the leading cause of hospitalization and death globally. CVD includes disturbances of the heart rhythm, cardiac valve pathologies, genetically driven malformations and, ultimately, peripheral artery disease (PAD) or coronary artery disease (CAD), which may culminate, respectively, in critical limb ischemia (CLI) and heart failure (HF). The use of cells with stem/progenitor characteristics in PAD and CLI has shown a success in clinical translation to a certain extent, given the ability of the chosen cells (e.g., derived from bone marrow, peripheral blood, or cord blood) to promote de novo vasculogenesis by a robust "paracrine effect". By contrast, the use of a similar setting to regenerate the contractile mass of the heart to compensate the loss of myocytes due to acute/chronic ischemia and/or inflammation has been largely unsuccessful and controversial, due to the absence of resident stem cells that could be activated in situ and/or expanded in vitro prior to being reinjected into the failing hearts.

Alternatives to this deficiency have been sought in the use of induced pluripotent stem cells (iPSCs), whose derived cardiomyocytes (CMs) have been employed in preclinical models in small and large animals, and even in pioneering studies in humans. Although scaled-up systems to produce therapeutic quantities of these cells with enhanced purity have been set, anticipating industrial production, several caveats have been expressed due to risks of arrhythmogenicity, incomplete maturation, potential tumor formation, and (at least for allogenic use) immune reactions.

Given the lack of endogenous regenerative capacity of the myocardium, the consequence of acute/chronic cardiac ischemia is still considered an irreparable damage leading to progressive replacement of the contractile cells with a stiff, fibrotic scar. Under these conditions, the heart undergoes a series of morphological transformations (e.g., rearrangement of the contractile apparatus and modification of the geometry), changes in mechanical characteristics and reduction of the pumping efficiency, representing signs of HF. With the advent of tissue engineering, the introduction of biological fabrication methods combined with refined systems for cellular genetic manipulation and decryption of mechanosensitive cues has enabled new strategies to enhance the efficacy of cardiac cell therapy and the elaboration of disease modeling systems using scaffolds, tissue printing, and tissue engineering approaches. This renews the hope that after the disappointment arising from the failure of the "classical" cell therapy approaches, it will be possible to reach a condition to regenerate the human heart, which still represents the "holy grail" of cardiology.

Senolytic Treatment Fails to Improve Measures of the Immune Response to Influenza in Old Mice
https://www.fightaging.org/archives/2023/07/senolytic-treatment-fails-to-improve-measures-of-the-immune-response-to-influenza-in-old-mice/

At this point in the development of senolytic therapies to clear harmful, lingering senescent cells from aged tissues, it is more interesting to find an aspect of aging that isn't improved by removal of senescent cells than to continue adding to the long list of age-related conditions and dysfunctions that are meaningfully reversed by senescent cell clearance. Here, researchers show that measures of the immune response to influenza infection in mice are not improved followed treatment with the senolytic combination of dasatinib and quercetin. This is a perhaps surprising result, given the expectation based on evidence to date that senolytics should improve immune function in later life.

Age is the greatest risk factor for adverse outcomes following influenza infection. The increased burden of senescent cells with age has been identified as a root cause in many diseases of aging and targeting these cells with drugs termed senolytics has shown promise in alleviating many age-related declines across organ systems. However, there is little known whether targeting these cells will improve age-related deficits in the immune system.

Here, we utilized a well characterized senolytic treatment with a combination of dasatinib and quercetin (D + Q) to clear aged (18-20 months) mice of senescent cells prior to influenza infection. We comprehensively profiled immune responses during the primary infection as well as development of immune memory and protection following pathogen reencounter. Senolytic treatment did not improve any aspects of the immune response that were assayed for including: weight loss, viral load, CD8 T-cell infiltration, antibody production, memory T cell development, or recall ability. These results indicate that D + Q may not be an appropriate senolytic to improve aged immune responses to flu infection.

Reviewing the Role of the Glymphatic System in Brain Aging
https://www.fightaging.org/archives/2023/07/reviewing-the-role-of-the-glymphatic-system-in-brain-aging/

That the brain has a lymphatic system is a comparatively recent realization. It coincides with another recent realization that perhaps drainage of fluid from the brain is important in maintaining brain health, carrying away molecular waste that would otherwise accumulate to cause pathology. Common age-related neurodegenerative diseases are characterized by rising inflammation and increasing presence of protein aggregates and other molecular waste in the brain, and it is now known that drainage pathways from the brain to the body are impaired with age. It remains to be seen how well restored drainage performs as a basis for therapy, though Leucadia Therapeutics nears human clinical trials of their implant to restore cerebrospinal fluid drainage through the cribriform plate, a different pathway from the glymphatic system that is more relevant to the onset of Alzheimer's disease.

It was traditionally believed that the lymphatic system didn't exist in the central nervous system. Thus, cell debris, potential neurotoxic proteins, and other metabolites with large molecular weight were considered to be removed in a different clearance pathway than brain vasculature. In 2012, the researchers found that cerebrospinal fluid (CSF) can enter brain parenchyma and exchange with brain interstitial fluid (ISF) in the presence of aquaporin-4 (AQP4) on astrocytes. Likewise, when the mixed fluid was drained from the brain, Amyloid-β (Aβ) was transported along with the outflow. Since the function of this "drainage" pathway is similar to that of the lymphatic system and supported by astrocytes, it was named the glymphatic system after the role of glia cells.

Since last decade, many researchers in the field of neurology, neurodegenerative diseases and physiology have aimed to study and develop the glymphatic system, providing a brand-new perspective for us to understand brain diseases: the overall fluid flow of the brain rather than a specific lesion or structure. Herein, we summarized the components of the glymphatic system, the fluid circulation mode within this system, how pathogenic solutes are transported in certain diseases, affecting factors of its function, and by what means we can study the glymphatic system. It may provide direction and reference for brain diseases and medical researchers.

Towards Depletion of Microglia as a Treatment for Alzheimer's Disease
https://www.fightaging.org/archives/2023/07/towards-depletion-of-microglia-as-a-treatment-for-alzheimers-disease/

In recent years, increasing attention has been given to the role of microglia in neurodegenerative conditions. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body, but which also participate in the organization of synaptic connections in addition to the other roles one might expect from immune cells. Microglia in the aging brain become more inflammatory and overactive with age. Some become senescent. This contributes to the chronic inflammation of brain tissue observed in older individuals, and which contributes to the onset and progression of neurodegenerative conditions. Interestingly, it is possible to efficiently clear microglia using CSF1R inhibitor drugs, after which the population is recreated over the course of a few weeks, lacking much of the dysfunction. This approach has yet to be earnestly tested as a way to help slow the progression of neurodegeneration, but the research community appears to be slowly moving in that direction.

It is evident that microglia are crucial players in the pathogenesis of Alzheimer's disease (AD), and a deeper understanding of their diverse functions and interactions with other cellular components in the brain will be vital for the development of effective therapeutic strategies. However, despite considerable progress in recent years, there remain significant gaps in our knowledge of microglial biology, particularly concerning their heterogeneity, precise mechanisms of action, and the interplay between various signaling pathways.

Multiple research studies have underscored the significance of specific subsets of microglia, particularly disease-associated microglia (DAM), in the progression of AD. The conjecture underpinning microglial depletion is that certain activated microglia, including DAM, may accentuate AD pathogenesis through a series of actions, such as facilitating the accumulation of Aβ plaques, amplifying neuroinflammation, and potentially influencing tau pathology. DAMs, characterized by a unique transcriptional profile and often found in close proximity to amyloid plaques, are thought to have substantial impacts on neuronal health and function. Consequently, it has been proposed that therapeutic strategies should be more disease-specific and aim at selectively targeting these DAMs.

The implementation of microglial depletion has been achieved through various strategies, most notably using pharmacological and genetic techniques. A common method involves the use of brain-penetrating inhibitors of CSF1R, a crucial cell surface receptor for microglial survival and proliferation. In AD mouse models, these inhibitors have demonstrated improvements in cognition and reductions in both neuroinflammation and neuritic plaque formation. However, the relationship between microglial depletion and amyloid pathology has been inconsistent, highlighting the need for further investigation. The potential of microglial depletion as a therapeutic approach must be carefully evaluated, but more research is warranted to further elucidate the complex roles of microglia, particularly DAM, in AD pathogenesis and treatment.

Mitochondrial Aging in the Context of Kidney Function
https://www.fightaging.org/archives/2023/07/mitochondrial-aging-in-the-context-of-kidney-function/

Mitochondria are responsible for producing the chemical energy store molecules, adenosine triphosphate (ATP), used to power cellular processes. Unfortunately, mitochondria become dysfunctional with age, in complex ways and for complex reasons that are not yet fully understood. Mitochondria evolved from symbiotic bacteria, and still act much like bacteria inside the cell. They carry a remnant circular genome, the mitochondrial DNA, they replicate as needed to keep their numbers up, they can fuse together and pass around component parts, they are recycled when worn or damaged by the quality control mechanisms of mitophagy. Within this dynamic system, age-related changes in gene expression and damage to mitochondrial DNA produces a growing loss of function. That in turn impacts the ability of organs in the body to function and maintain themselves.

Aging is an inevitable life process. The ability of aging organs to resist adverse external stimuli decreases, and thus they are more vulnerable to damage. Mitochondrial homeostasis plays an indispensable role in maintaining kidney function, and when mitochondrial function is disturbed, it will accelerate the aging of renal cells. Here, we reviewed the evidence of renal mitochondrial disorders, including abnormal mitochondrial function, abnormal mitophagy, and abnormal activation of oxidative stress and inflammation in renal aging.

Although targeting mitochondria is a potential strategy to slow kidney aging, many questions remain to be addressed, such as what role mitochondrial DNA (mtDNA) plays in renal aging. Although current studies have shown that inhibiting the release of mtDNA can inhibit the activation of inflammation and the occurrence of aging in other tissues and cells, there has been no research on the role of mtDNA in renal aging. Moreover, identifying specific renal mitophagy activators is also needed. Current studies have been conducted on animal and cell models, and there may be significant differences in the aging process and immune system between species that could limit the applicability of these findings to humans. Therefore, the relationship between aging and mitochondrial abnormalities in kidney tissue needs to be clarified in future studies.

When these questions are thoroughly investigated and answered, targeting mitochondria as a strategy to alleviate kidney aging will be viable. In addition, given the importance of mitochondria in biological activity and aging, targeting mitochondria may be a strategy for delaying aging in organs other than the kidney.

Developing a Recellularization Approach to Produce Thymic Tissue
https://www.fightaging.org/archives/2023/07/developing-a-recellularization-approach-to-produce-thymic-tissue/

The thymus produces the T cells that make up the adaptive immune system, but the organ atrophies with age, contributing to the age-related decline of immune function. A popular science article here comments on a new biotech company seeking to produce thymus tissue for transplantation from decellularized donor tissues. This builds upon work of recent years that improves the understanding of the stem cell and progenitor cell populations that give rise to thymic tissue. Given that understanding, it should be possible to take decellularized thymic tissue and repopulate it with patient-derived cells, or from novel universal cell lines that have been altered so as to allow transplantation into any individual with minimal risk of rejection. While it seems likely that the company will, at the end of the day, remain focused entirely on children born without a thymus rather than on the age-related loss of thymic tissue, there is certainly that potential application waiting in the wings for someone to take up the flag and run with it.

"The thymus had largely been ignored because it's complicated, and historically understanding of the biology had progressed slowly. It's starting to accelerate now and a lot of the work that the Francis Crick Institute has been doing is aimed at understanding the core stem cell niche of the thymus and use this to recreate thymus biology. Until recently, there was uncertainty around the progenitor stem cell that leads to the epithelial cells that gives the thymus function. The Crick researchers discovered novel progenitor cells and Videregen has licensed the resulting patents, which give us the basis of the cell biology. That allows us to build a better functioning thymus from scratch, because we understand the cell biology better than anyone else."

The initial indication for Videregen's immune program is children born without thymus function, which is called complete DiGeorge Syndrome, but this is only the beginning of the company's work in this area. "The thymus is primarily concerned with two things: the first is to provide T cells, which fight infection and circulate our bodies throughout our life, taking out precancerous cells. Over time, our thymus function decreases, which is why in old age, you tend to get more cancers, you respond less well to vaccines, and you get more infections. So addressing thymus atrophy is a big factor in longevity and aging. At the moment, we're focusing on niche, orphan indications, which means we don't need to industrialize to a big scale - we're talking about hundreds or thousands of patients, not millions. But when we get to those kinds of scales of populations, we will need the technology to be able to deliver a mass-produced tissue."

Videregen's approach is built on the company's expertise in decellularization - the process used to isolate the extracellular matrix of a tissue from its inhabiting cells, leaving only a "scaffold" of the original tissue. This scaffold can then be seeded with appropriate cells to enable organ and tissue regeneration. "We've learned that the biology of the extracellular matrix is really important - it isn't just structural. If you preserve the biology well, you get better infiltration of cells, better vascularization, and better repair and function over time. This is achieved by controlling the way the tissue is processed and decellularized - the more natural the better."

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