Fight Aging! Newsletter, November 6th 2023

Historically, much scientific work interrogating the homeostatic roles of the nervous system focused on neurons. While it is clear that glia, the other main cell type of the nervous system, can serve many roles in neuronal development and function, these roles are normally associated with support roles, including regulating cell number, neuronal migration, axon specification and growth, synapse formation and pruning, ion homeostasis, and synaptic plasticity and providing metabolic support for neurons. However, in recent years, it has become increasingly clear that glial health can affect aging and progression of neurodegenerative diseases, like Alzheimer's disease (AD).

For example, expression of apolipoprotein E4 (ApoE4), one of the strongest risk factors for AD, specifically in astrocytes resulted in increased neuronal tau aggregation. Moreover, hyperactivation of the unfolded protein response of the endoplasmic reticulum (UPRER), which drives ER stress resilience, solely in astrocyte-like glial cells resulted in a significant life-span extension in Caenorhabditis elegans. While these studies show the importance of glial function in organismal health, what they lacked is an active function of glia in promoting these beneficial effects.

To uncover an active role for glia in stress signaling and longevity, we aimed to determine whether glial cells can sense mitochondrial stress and initiate an organism-wide response to promote mitochondrial stress resilience and longevity. We used multiple genetic methods to activate the mitochondrial unfolded protein response (UPRMT) in nonneuronal cells, including cell-type-specific application of mitochondrial stress and direct activation of the UPRMT in the absence of stress.

We found that, regardless of method, activation of UPRMT in a small subset of glial cells, the cephalic sheath glia, provided robust organismal benefits, including prolonged life span and increased resistance to oxidative stress. Perhaps most unique in this model is that UPRMT activation in cephalic sheath glia promotes neuronal health by alleviating protein aggregation in neurons of a Huntington's disease (HD) model. Cephalic sheath glia directly communicate with neurons through the release of small clear vesicles (SCVs) and relay the coordination to the periphery via downstream neuronal mechanisms. This glia to neuron signal results in induction of the UPRMT in distal tissues, through a cell nonautonomous mechanism, which is dependent on the canonical UPRMT pathway, yet unexpectedly distinct from paradigms where UPRMT is directly activated in neurons.

Collectively, these results reveal a previously unknown function for cephalic sheath glia in sensing mitochondrial stress, which initiates a signal to promote protein homeostasis in neurons and ultimately prolongs longevity. Therefore, glial cells serve as one of the upstream mediators of mitochondrial stress and its coordination across the entire organism.

Aging impairs the heart's ability to repair and regenerate. As people age, their cardiac stem cells, i.e. cardiac progenitor cells (CPCs), become senescent, upregulating key markers of senescence, such as p16Ink4a and senescence-associated β-galactosidase, and markers of DNA damage, such phosphorylated histone 2AX. Senescent CPCs also possess critically short telomeres and a senescence-associated secretory phenotype (SASP). Indeed, by the time a person is 75 years old, approximately 50% of their CPCs are senescent. Cardiac progenitor cells from older patients are dysfunctional, showing impaired growth, clonogenicity, and cardiomyogenic differentiation potential. When senescent human CPCs were transplanted into a myocardial-infarcted mouse heart, there was decreased cardiac regeneration and cardiac function compared with when non-senescent CPCs were transplanted.

Next, the effects of senolytics and global senescent cell removal on the aged heart were determined. In this experiment, 24- to 32-month-old wild-type mice were randomly assigned to vehicle or senolytic dasatinib and quercetin (D+Q) treatment, administered in 4 cycles at 3 consecutive days per cycle, with the cycles occurring 12 days apart. P16Ink4a messenger RNA expression decreased in the heart following D+Q treatment in older mice. Morphometric analysis of heart sections showed that D+Q-treated mice had decreased fibrosis and hypertrophy and that senolytic treatment had induced compensatory cardiomyocyte renewal and replacement. An increased number of smaller ventricular 5-ethynyl-2ʹ-deoxyuridine-positive or Ki-67-positive cardiomyocytes were found, suggesting that these mice had cardiomyocytes that were immature and newly formed compared with vehicle-treated mice, which exhibited only rare, small 5-ethynyl-2ʹ-deoxyuridine-positive or Ki-67-positive cardiomyocytes but a greater proportion of hypertrophied myocytes. Finally, D+Q treatment rejuvenated the heart's regenerative potential, activating and increasing the number of CPCs.

The present findings support targeting senescence using senolytics to prevent, delay, and treat multiple age-related heart disorders as well as the toxic and senescence-inducing effects of cancer chemotherapy on the heart. Clinical trials on senolytics are already underway. The Translational Geroscience Network in the United States is conducting 15 clinical studies on senolytics for age-related conditions. They have developed assays for measuring biomarkers in the blood and tissues that can be used to test the efficacy of senolytics in the proposed trials and to identify people who are most likely to benefit from senolytic therapy. Research into understanding how senolytics act on the human heart, in clearing senescent cells, or whether they have any off-target side effects is greatly needed.

Like most tissue regenerative processes, the regenerative capacity of tendons decreases with aging or even fails and is often accompanied by stem cell exhaustion and cellular senescence. The regenerative capacity of adult tendons depends on the status of stem/progenitor cells (TSPCs), which can activate and expand to form new tendon collagen fibers or self-renew to restore the TSPC pool in response to tissue damage. At later stages in life, TSPCs present a marked impairment of stemness and regenerative capacity, resulting in inefficient tendon self-repair. In previous research, we found that the difference in TSPC stemness between the neonatal and adult stages influenced multiple biological functions of TSPCs and the adult tendon regenerative process.

In this context, a reasonable stemness-modulating method is a prospective strategy for remedying aged TSPCs. Traditionally, the dampened stemness can only be reversed by inducing Yamanaka factors genetically. However, an efficient strategy to identify stemness-promoting small molecules is currently lacking. In recent years, deep learning approaches have been widely applied in target-based drug design and for the development of various therapeutic strategies. However, these methods cannot be used when the target is unknown; for instance, with regard to stemness promotion, only four transcription factors are known. In this study, we employed the newly developed system, DLEPS, which is an efficacy prediction system using transcriptional profiles with deep learning, to identify potential drugs to stimulate stemness.

In our study, we found that the top-ranked candidate compound prim-O-glucosylcimifugin (POG) could efficiently inhibit TSPC senescence and promote their tenogenic differentiation potential in an in vitro serial passaging cell senescence model. We also found that the top-ranked POG potently rejuvenated the proliferation and tenogenic potential of TSPCs from both aged rats and middle-aged humans by maintaining stemness and suppressing senescence.

Generally, the results from multiple senescent cell models provide solid and convincing evidence that POG is indeed a potent antisenescent drug for TSPCs. Moreover, the systemic administration of POG and the local delivery of POG encapsulated in nanoparticles were found to promote aged tendon self-repair in small-sized, partial transection tendon injuries. The combination of POG administration and the transplantation of scaffolds significantly enhanced the aged endogenous regenerative capacity in large-sized, full-cut tendon window defects in aged rats. These findings provide multiple alternative strategies for endogenous tendon repair and regeneration in aging according to different injury conditions.

DNA methylation (DNAm) age acceleration (AgeAccel) and cardiac age by 12-lead advanced electrocardiography (A-ECG) are promising biomarkers of biological and cardiac aging, respectively. We aimed to explore the relationships between DNAm age and A-ECG heart age and to understand the extent to which DNAm AgeAccel relates to cardiovascular (CV) risk factors in a British birth cohort from 1946.

We studied four DNAm ages (AgeHannum, AgeHorvath, PhenoAge, and GrimAge) and their corresponding AgeAccel. Outcomes were the results from two publicly available ECG-based cardiac age scores: a Bayesian A-ECG-based heart age score and a deep neural network (DNN) ECG-based heart age score. DNAm AgeAccel was also studied relative to results from two logistic regression-based A-ECG disease scores, one for left ventricular (LV) systolic dysfunction (LVSD), and one for LV electrical remodeling (LVER). Generalized linear models were used to explore the extent to which any associations between biological cardiometabolic risk factors (body mass index, hypertension, diabetes, high cholesterol, previous cardiovascular disease [CVD], and any CV risk factor) and the ECG-based outcomes are mediated by DNAm AgeAccel.

By the age of 60, participants with accelerated DNA methylation appear to have older, weaker, and more electrically impaired hearts. We show that the harmful effects of CV risk factors on cardiac age and health, appear to be partially mediated by DNAm AgeAccelPheno and AgeAccelGrim. This highlights the need to further investigate the potential cardioprotective effects of selective DNA methyltransferases modulators.

The field of targeting cellular senescence with drug candidates to address age-related comorbidities has witnessed a notable surge of interest and research and development. This study aimed to gather valuable insights from pharmaceutical experts and healthcare practitioners regarding the potential and challenges of translating senolytic drugs for treatment of vascular aging-related disorders. This study employed a qualitative approach by conducting in-depth interviews with healthcare practitioners and pharmaceutical experts. Participants were selected through purposeful sampling. Thematic analysis was used to identify themes from the interview transcripts. A total of six individuals were interviewed, with three being pharmaceutical experts and the remaining three healthcare practitioners.

Health providers and pharmaceutical experts viewed that there are certain challenges and considerations associated with measuring outcomes and assessing the effects of senolytic therapies. One of the primary issues is that measurable outcomes may not be immediate. Senescent cell clearance and subsequent tissue regeneration may take time to manifest noticeable effects. More importantly, to date there are no tools such as imaging probes or biomarkers that can measure the clearance of senescent cells from tissue. The lack of such simple tools not only hamper the identification of senolytic drugs which are truly specific for senescent cells but also for monitoring therapeutic efficacy.

Results from completed trials of dasatinib and quercetin using intermittent dosing (i.e., consecutive treatment for 2-3 days with 2-week resting period) appears to be tolerable, with mild to modest adverse effects. Hence, it is crucial to establish the safety profile and dosing regimen of new senolytic drugs to harness the beneficial effects whilst minimizing risks. From the healthcare practitioners' perspective, it is crucial to ensure that the new senolytic therapy does not interact with other medications, particularly for elderly individuals who are already managing multiple conditions and taking numerous medications. While drug interaction profiles may be available for repurposed drugs, it may not the case for newly developed senolytics. To this end, potential drug-drug interactions, particularly with medications taken by the elderly individuals for their comorbidities have yet to be examined in preclinical and clinical studies and warrant future investigations. In this regard, pharmaceutical experts of this study pointed out the importance of addressing both the selectivity and specificity of senolytics. Improving senolytics selectivity for senescent cells while sparring healthy non-senescent cells is crucial to minimize potential side effects.

The pharmaceutical sector demonstrates a positive inclination towards the commercialization of new senolytic drugs, albeit with concerns around safety and efficacy. Besides sharing the same outcome-related concerns as with the pharmaceutical experts, healthcare practitioners anticipated a lack of awareness among the general public regarding the concept of targeting cellular senescence to delay vascular aging-related disorders, and this knowledge gap extends to healthcare practitioner themselves as well.

Heart attacks occur when blood flow in the coronary arteries is blocked, resulting in an inadequate supply of nutrients and oxygen to the heart muscle, and ultimately death of cardiac myocytes. To prevent this, cardiac myocytes use a process known as autophagy to dispose of damaged cellular components, keeping them from causing cardiac dysfunction. Previous studies have shown that the periodontal pathogen Porphyromonas gingivalis, which has been detected at the site of occlusion in myocardial infarction, can exacerbate post-infarction myocardial fragility. However, the mechanisms underlying this effect remained unknown.

To investigate this, researchers created a version of P. gingivalis that does not express gingipain, its most potent virulence factor, which an earlier study showed can inhibit cells from undergoing programmed cell death in response to injury. They then used this bacterium to infect cardiac myocytes or mice. "The results were very clear. The viability of cells infected with the mutant bacterium lacking gingipain was much higher than that of cells infected with the wild-type bacterium. In addition, the effects of myocardial infarction were significantly more severe in mice infected with wild-type P. gingivalis than in those infected with the mutant P. gingivalis lacking gingipain."

More detailed investigation of this effect showed that gingipain interferes with fusion of two cell components known as autophagosomes and lysosomes, a process that is crucial to autophagy. In mice, this resulted in an increase in the size of cardiac myocytes and accumulation of proteins that would normally be cleared out of the cells to protect the cardiac muscle. "Our findings suggest that infection with P. gingivalis producing gingipain results in excessive autophagosome accumulation, which can lead to cellular dysfunction, cell death, and ultimately cardiac rupture."

During the 1910s three buffalofish species (Catostomidae: Ictiobus cyprinellus, I. bubalus, I. niger) were reared in ponds along the Mississippi River. Individuals of these buffalofishes were transported to locations across the United States to support or establish commercial fisheries, including Roosevelt Lake, Arizona in 1918. During the 1930s-1960s a commercial fishery existed on Roosevelt Lake, ending by 1970. Scarce information exists on Arizona buffalofishes since.

From 2018 to 2023 we studied buffalofishes from nearby Apache Lake (adjacent and downstream of Roosevelt Lake) in collaboration with anglers. Here we show that more than 90% of buffalofishes captured from Apache Lake are more than 80 years old and that some of the original buffalofishes from the Arizona stocking in 1918 are likely still alive. Using unique markings on old-age buffalofishes, we demonstrate how individuals are identified and inform dozens of recaptures. With a sample size of only 23 individuals across the three species of buffalofishes at Apache Lake, we found direct evidence of centenarian longevity for black buffalo (108 years), bigmouth buffalo (105 years), and smallmouth buffalo (101 years).

We now know all species of USA Ictiobus can live more than 100 years, making it the only genus of animal besides marine rockfishes (Sebastes) for which three or more species have been shown to live more than 100 years. Our citizen-science collaboration has revealed remarkable longevity for freshwater fishes and has fundamentally redefined our understanding of the genus Ictiobus itself.

Engineered gut microbiota represents a new frontier in medicine, in part serving as a vehicle for the delivery of therapeutic biologics to treat a range of host conditions. The gut microbiota plays a significant role in blood pressure regulation; thus, manipulation of gut microbiota is a promising avenue for hypertension treatment. In this study, we tested the potential of Lactobacillus paracasei, genetically engineered to produce and deliver human angiotensin converting enzyme 2 (Lacto-hACE2), to regulate blood pressure in a rat model of hypertension with genetic ablation of endogenous Ace2 (Ace2-/- and Ace2-/y).

Our findings reveal a sex-specific reduction in blood pressure in female (Ace2-/-) but not male (Ace2-/y) rats following colonization with the Lacto-hACE2. This beneficial effect of lowering blood pressure was aligned with a specific reduction in colonic angiotensin II, but not renal angiotensin II, suggesting the importance of colonic Ace2 in the regulation of blood pressure. We conclude that this approach of targeting the colon with engineered bacteria for delivery of ACE2 represents a promising new paradigm in the development of antihypertensive therapeutics.

Experimental studies in animal models of aging such as nematodes, fruit flies, or mice have observed that decreased levels of insulin or insulin signaling promotes longevity. In humans, hyperinsulinemia and concomitant insulin resistance are associated with an elevated risk of age-related diseases suggestive of a shortened healthspan. Age-related disorders include neurodegenerative diseases, hypertension, cardiovascular disease, and type 2 diabetes. High ambient insulin concentrations promote increased lipogenesis and fat storage, heightened protein synthesis, and accumulation of non-functional polypeptides due to limited turnover capacity. Moreover, there is impaired autophagy activity, and less endothelial NO synthase activity. These changes are associated with mitochondrial dysfunction and oxidative stress.

The cellular stress induced by anabolic activity of insulin initiates an adaptive response aiming at maintaining homeostasis, characterized by activation of the transcription factor Nrf2, of AMP activated kinase, and an unfolded protein response. This protective response is more potent in the long-lived human species than in short-lived models of aging research resulting in a stronger pro-aging impact of insulin in nematodes and fruit flies. In humans, resistance to insulin-induced cell stress decreases with age, because of an increase of insulin and insulin resistance levels but less Nrf2 activation. These detrimental changes might be contained by adopting a lifestyle that promotes low insulin/insulin resistance levels and enhances an adaptive response to cellular stress, as observed with dietary restriction or exercise.

Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype.

We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.

With their continuous production of the senescence-associated secretory phenotype (SASP), senescent cells (SnCs) hinder tissue renewal and accelerate pathological deterioration, thus damaging the development and maintenance of functional ability, which is the major concern of healthy aging. The immune system primarily takes the responsibility of identifying and recycling irregular cells, thus ensuring an endogenous approach to achieve healthy aging. However, the immunosurveillance function gradually loses its balance with cellular and microenvironmental changes in the aging process, indulging the irreversible aging process. Hence, the restoration and mobilization of immunosurveillance could be an entry point to boost healthy aging.

Cytotoxic T lymphocytes (CTLs), as an important part of the immune system, mainly include CD4+ CTLs, CD8+ CTLs, and artificially modified cytotoxic chimeric antigen receptor T cells (CAR T cells). CTLs bind with antigen-presenting target cells, releasing perforin and granzyme which induce the death of target cells. Studies have suggested the well-established role of CTLs in eliminating cancer cells selectively. Could this theory be applied to the elimination of SnCs effectively? p21, a classical marker of cellular senescence, was found to induce CXCL14 and other immune-modulatory factors expression in hepatocytes. These immune modulatory factors further boosted M1 macrophage differentiation and the recruitment of CTLs to p21-expressing hepatocytes, strongly suggesting that CTLs may contribute to the immune clearance of SnCs

Immunosurveillance on aging is a complex yet poorly understood natural process. Revealing attempts have been made to identify prominent senescent hallmarks that activate CTLs. Furthermore, the demonstration of how SnCs are eliminated by CTLs in natural processes offers potential interference approaches. The exploratory application of immune checkpoint blockade and CAR T cells provides strategies to prevent SnCs from escaping immunosurveillance. With the discovery of new aging hallmarks and successful mobilization of CTLs, future senolysis may contribute to healthy aging and prevent aging-related diseases.

The development of sarcopenia in the elderly is associated with many potential factors and/or processes that impair the renovation and maintenance of skeletal muscle mass and strength as ageing progresses. Among them, a defect by skeletal muscle to respond to anabolic stimuli is to be considered. Common anabolic stimuli/signals in skeletal muscle are hormones (insulin, growth hormones, IGF-1, androgens, and β-agonists such epinephrine), substrates (amino acids such as protein precursors on top, but also glucose and fat, as source of energy), metabolites (such as β-agonists and HMB), various biochemical/intracellular mediators), physical exercise, neurogenic and immune-modulating factors, etc. Each of them may exhibit a reduced effect upon skeletal muscle in ageing.

In this article, we overview the role of anabolic signals on muscle metabolism, as well as currently available evidence of resistance, at the skeletal muscle level, to anabolic factors, from both in vitro and in vivo studies. Some indications on how to augment the effects of anabolic signals on skeletal muscle are provided.

This study assessed the effect of normal aging and neuroinflammation on the medial septal Iba-1+ microglia population and the consequential effect on the choline acetyl transferase (ChAT)+ cholinergic cell population. Chronic IL-6 expression in the mouse brain significantly increased the reactive Iba-1+ microglia and decreased the ChAT+ cholinergic cell number in the medial septum and this tendency exacerbated with aging. We also showed that aging and chronic IL-6 expression reorientated the septal microglia morphology towards a more reactive and de-ramified pro-inflammatory phenotype.

These findings further reflected upon the septal cholinergic cell population displaying a neurodegenerative phenotype. The resultant direct effect of neuroinflammation and aging on the septal cholinergic population mirrored upon the hippocampal pyramidal cell dendritic spine density. Overall, these findings demonstrate a potential detrimental effect of chronic microglia activation on the medial septum, which can exacerbate throughout aging, leading to cholinergic dysfunction that could in turn disrupt hippocampal pyramidal cell network regulation.

A team of researchers studying the Ngogo community of wild chimpanzees in western Uganda's Kibale National Park for two decades has published a report showing that females in this population can experience menopause and postreproductive survival. Prior to the study these traits had only been found among mammals in a few species of toothed whales, and among primates only in humans. These new demographic and physiological data can help researchers better understand why menopause and post-fertile survival occur in nature, and how it evolved in the human species.

The grandmother hypothesis has been used to explain the existence of human postmenopausal survival, proposes that females in their postreproductive years may be able to pass on more of their genes by helping to raise the birth rates of their own children or by caring directly for grandchildren, thereby increasing grandchildren's odds of survival. And indeed, several studies of human grandmothers have found these positive effects. But chimpanzees have very different living arrangements than humans. Older female chimpanzees typically do not live near their daughters or provide care for grandchildren, yet females at Ngogo often live past their childbearing years.

While substantial postreproductive life spans have not previously been observed in other long-term studies of wild chimpanzees, they have sometimes been seen in chimpanzees and other primates in captivity, who receive good nutrition and medical care. This raises the possibility that the postreproductive life spans of female Ngogo chimpanzees may be a temporary response to unusually favorable ecological conditions, as this population enjoys a stable and abundant food supply and low levels of predation. Another possibility, however, is that postreproductive life spans are actually an evolved, species-typical trait in chimpanzees but have not been observed in other chimpanzee populations because of the recent negative impacts of humans.

Age remains the largest risk factor in the development of neurodegenerative diseases such as Alzheimer's disease (AD). Numerous cellular hallmarks of aging contribute to the advancement of the pathologies associated with neurodegenerative disease. Not all cellular hallmarks of aging are independent and several fall into the broader category of cellular rejuvenation, which captures returning cells to a more youthful, improved functional state. Cellular rejuvenation is quickly becoming a hot topic in the development of novel therapeutic modalities for a range of diseases. Therapeutic approaches that utilize cellular rejuvenation technologies are rapidly advancing and will represent the next phase of AD therapeutics.

This review focuses on two important processes, epigenetic reprogramming, and chaperone-mediated autophagy (CMA) that play a critical role in aging and in neurodegenerative diseases and the potential therapeutic approaches (gene therapy, small molecule) towards targeting these mechanisms. In aging and in AD, epigenetic changes on DNA (e.g., hypermethylation on CpG islands) lead to alterations in gene expression. Partial epigenetic reprogramming utilizes transcription factors to remove the epigenetic marks and to rejuvenate cells to a more youthful state. During aging and in neurodegenerative disorders, CMA becomes impaired resulting in a buildup of proteins known to be associated with neurodegenerative pathologies. The protein buildups lead to aggregates that preclude proteostasis leading to cell toxicity. Small-molecule CMA activators restore proteostasis and limit toxicity enabling cellular rejuvenation.