Fight Aging! Newsletter, May 13th 2024

While the concept that mature cell states are stable holds the key for homeostasis of an organism, the long-held believe was that this state cannot ever be reversed. This fallacy has gradually broken down. Now, the Yamanaka factors are now widely used not only for reprogramming but also for partial reprogramming that leads to rejuvenation of tissues. Yet another kind of reprogramming was emerging from the basic science field, now dubbed direct reprogramming, or transdifferentiation (we use the terms interchangeably from here on). During transdifferentiation a differentiated cell changes its fate to another, more desired differentiated cell type, without entering a pluripotent stage. The first identified transcription factor capable of directly reprogramming fibroblasts to skeletal muscles was MyoD. Many other lineage-specific transcription factors capable of transdifferentiating a target cell have since been identified.

Whether induced or endogenous process, in general, pioneer factors (PF) act as the first responders in direct reprogramming by binding and opening closed chromatin. It is not clear if each transdifferentiation lineage is regulated by a specific pioneer factor, or if a universal PF for transdifferentiation (capable of initiating multitude of direct lineage reversions) is still to be identified. Transdifferentiation studies have unveiled the opportunities and offer applications in regenerative therapies, such as cell replacement therapy or immunotherapy. The key question, and the topic of this review is to identify new, feasible methods to induce specific, high efficiency and targeted transdifferentiation.

These next-generation transdifferentiation approaches will come with better efficiency and plausibly with potential to treat diseases like Alzheimer's disease, muscle injury, diabetes, or myocardial infarction, resulting in elimination of the unsurmountable treatment issues at the moment (for example, finding a right donor or graft rejections). These novel approaches will enhance the efficacy and safety of direct reprogramming, allowing the ultimate decoding of the process towards plausibly resulting in 21st century personalized regenerative medicine.

Local immune processes within aging tissues are a significant driver of aging associated dysfunction, but tissue-autonomous pathways and cell types that modulate these responses remain poorly characterized. The cytosolic DNA sensing pathway, acting through cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING), is broadly expressed in tissues, and is poised to regulate local type I interferon (IFN-I)-dependent and independent inflammatory processes within tissues. Recent studies suggest that the cGAS/STING pathway may drive pathology in various in vitro and in vivo models of accelerated aging.

To date, however, the role of the cGAS/STING pathway in physiological aging processes, in the absence of genetic drivers, has remained unexplored. This remains a relevant gap, as STING is ubiquitously expressed, implicated in multitudinous disorders, and loss of function polymorphisms of STING are highly prevalent in the human population (an incidence of more than 50%). Here we reveal that, during physiological aging, STING-deficiency leads to a significant shortening of murine lifespan, increased pro-inflammatory serum cytokines and tissue infiltrates, as well as salient changes in histological composition and organization.

We note that aging hearts, livers, and kidneys express distinct subsets of inflammatory, interferon-stimulated gene (ISG), and senescence genes, collectively comprising an immune fingerprint for each tissue. These distinctive patterns are largely imprinted by tissue-specific stromal and myeloid cells. Using cellular interaction network analyses, immunofluorescence, and histopathology data, we show that these immune fingerprints shape the tissue architecture and the landscape of cell-cell interactions in aging tissues. These age-associated immune fingerprints are grossly dysregulated with STING-deficiency, with key genes that define aging STING-sufficient tissues greatly diminished in the absence of STING. This altered homeostasis in aging STING-deficient tissues is associated with a cross-tissue loss of homeostatic tissue-resident macrophage (TRM) populations in these tissues. Ex vivo analyses reveal that basal STING- signaling limits the susceptibility of TRMs to death-inducing stimuli and determines their in situ localization in tissue niches, thereby promoting tissue homeostasis.

Collectively, these data upend the paradigm that cGAS/STING signaling is primarily pathological in aging and instead indicate that basal STING signaling sustains tissue function and supports organismal longevity. Critically, our study urges caution in the indiscriminate targeting of these pathways, which may result in unpredictable and pathological consequences for health during aging.

Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies.

While a mayfly has a lifespan of one day, an elephant's lifespan may exceed 100 years. Clearly, lifespan and aging are biological traits regulated by genetics and molecular signaling pathways - that may be exploited as a therapeutic target. Aging, however, is not recognized as a disease by the U.S. Food and Drug Administration. Thus, there are no FDA-approved treatments specifically for aging. Aging, however, is the most important risk factor for multiple diseases, including dementia and AD. As molecular mechanisms regulating aging are coming to light and signaling pathways uncovered, novel therapeutic targets present an alternative approach: instead of targeting one disease at a time - leading to the inconvenience, cost, and risk of polypharmacy - targeting aging directly may prevent or slow multiple age-related diseases. CR may be a promising preventive or therapeutic option for individuals at risk for AD or already within the AD spectrum. However, current data are limited and human studies are scarce. Additional preclinical and human studies are now warranted to discover the pathways regulated by CR and to identify pharmacophores that mimic the beneficial effects of CR.

Hypotheses linking CR and weight loss to alterations in biomarkers of aging and AD may suggest novel treatment targets and strategies-and not just for AD. Newly discovered therapies may be safe and effective for prevention and/or as an adjunct to FDA-approved treatments for individuals in the AD spectrum. Prevention and treatment strategies targeting aging may be safer and more effective than the currently available treatments targeting more downstream pathways. While several studies are in progress (listed above), more are needed. In the meantime, AD trials should consider including biomarkers of aging and aging studies should include AD biomarkers.

Alzheimer's disease (AD) is the most common form of dementia, affecting an estimated 6.5 million Americans including more than 10% of Americans over 65 years of age. There are no therapies that demonstrably stop the disease despite hundreds of clinical trials. The recent identification of reverse transcriptase (RT)-mediated somatic gene recombination (SGR) in the human brain, which becomes dysregulated in sporadic AD, implicates FDA-approved reverse transcriptase inhibitors (RTIs) as potential therapeutics for AD.

Multiple FDA-approved RTIs, the first of which was approved in 1987, are currently used to treat human immunodeficiency virus (HIV) and hepatitis B. RTIs can be orthosteric (bind to the active site) nucleoside RTIs (NRTIs) or allosteric non-NRTIs (NNRTIs), and together with integrase inhibitors and protease inhibitors (PIs), represent the components of combined antiretroviral therapy (cART). Because of effective cART, tens of thousands of people with HIV have lived to older ages but are now at risk for AD, providing an opportunity to retrospectively examine the incidence of AD by assessing medical claims databases.

This retrospective, proof-of-concept study evaluated the incidence of AD in people with HIV with or without exposure to NRTIs using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy.

We identified a statistically significant positive association between NRTI exposure and decreased risk for sporadic AD in patients with HIV and ≥60 years of age. Age-adjusted and sex-adjusted hazard ratio (HR) showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88) and 3 (HR 0.84). Post-marketing surveillance of NRTIs has shown acceptable safety data sufficient to allow NRTIs to be prescribed, as a class, continuously since 1987, and tens of thousands of patients ≥60 years of age are currently taking these medications, providing support that these agents will be well tolerated in aged patients. The data presented here support controlled clinical trials using NRTIs on patients with mild cognitive impairment (MCI), pre-symptomatic familial AD, Down syndrome, and sporadic AD, along with asymptomatic APOE4 carriers.

Final 12-month data from the EXACT trial demonstrates safety and efficacy results for a vascular endothelial growth factor (VEGF) gene therapy treatment for patients who have advanced coronary artery disease (CAD). CAD, also known as coronary heart disease or ischemic heart disease, affects about 20.5 million U.S. adults - making it the most common type of heart disease in the United States. Often, the first sign of CAD is a heart attack, triggered by a rupture of plaque accumulated in the arteries supplying blood to the heart. Over time, plaque narrows these arteries, blood flow diminishes, leading to angina - a condition characterized by chest pain due to insufficient oxygen-rich blood supply to the heart muscle. In patients with the most severe form, angina can be disabling, and additional medications, procedures or surgery may not be effective. There is a need for therapies for such a serious condition.

The EXACT trial assesses the safety and preliminary efficacy of the gene therapy XC001 in patients with "no option" refractory angina (NORA). The gene vector is designed to more effectively and safely increase the body's own signal for new blood vessel growth. Effectiveness was measured primarily by exercise capacity, degree of impairment of blood flow to the heart, and angina frequency and severity. Among the 32 patients with NORA, the gene therapy XC001 appeared safe with no serious adverse effects due to the drug. Surgical delivery was generally well-tolerated. Early benefits of XC001 are promising in relation to improvements in exercise duration, decreased symptoms, and improved blood flow in patients' hearts.

Total exercise duration increased from a mean of 359.9 seconds at baseline to 448.2 at three months, 449.2 at six months, and 477.6 at 12 months. Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% at three months, 14.3% at six months, and 10.2% at 12 months - demonstrating a reduction in impaired blood flood. The time to onset of ST depression during exercise tolerance testing increased by 105.2 at three months, 113.6 at six months, and 103.1 seconds at 12 months. Angina frequency decreased by -7.7 at three months, -6.6 at six months, and -8.8 episodes at 12 months. Angina class improved in 81% of participants at six months.

One major barrier to longevity research is evaluating the impact of interventions that improve human health and longevity because they are complex processes that occur over long time scales. Instead, measurable phenotypic traits or proxies of longevity, termed longevity biomarkers, may be used to assess the effectiveness of longevity interventions, or prognosticate clinical outcomes. Longevity biomarkers are critical tools for predicting lifespan and susceptibility to age-related diseases, but there exist a dizzying array of options, with at times contradictory readouts, and other key weaknesses.

Strengths of longevity biomarkers include providing insight into an individual's biological age, as opposed to chronological age, which is pivotal in evaluating targeted interventions that address aging and age-related conditions. However, most longevity biomarkers also exhibit notable weaknesses, such as a lack of specificity and lack of standardization across different studies and applications. These weaknesses underscore the need for more research to enhance their accuracy and reliability in long-term longitudinal studies.

In the present review, we discuss key strengths and weaknesses of popular clinical biomarkers used to predict morbidity and mortality associated with advanced age, identify existing bottlenecks, and integrate the field consensus on further directions for robust lifespan and healthspan estimation.

Cellular immunotherapy is revolutionizing oncology by harnessing T cells' unique ability to specifically target and potentially cure metastatic cancer, a feat not achievable with traditional treatments. Living T cells have proven they can eradicate even the most stubborn metastatic cells. However, challenges persist, as these therapies sometimes fail when T cells do not endure, often succumbing to exhaustion or senescence. This issue is being addressed by researchers who are exploring methods to enhance T cell resilience and functionality.

Evolution has shaped T cells to occasionally dampen their function in chronic viral infections to prevent autoimmunity and mitigate potential harm from an overly aggressive immune response. For example, the immune system's complete elimination of a hepatitis virus could cause significant liver damage. Chronic activation can also drive T cells toward senescence and exhaustion, weakening the immune response to cancer. To address these challenges, researchers have developed checkpoint inhibitors and engineered T cells to create synthetic T cells that can reverse or bypass these evolutionary constraints with great success in some indications.

Researchers have developed a synthetic T cell state they call TIF (T cells with an immortal-like and functional state). TIF cells are the product of disrupting the BCOR and ZC3H12A genes, a result that is surprising because these genes are typically expressed at low levels in T cells and lack dynamic regulation. This approach is aimed at addressing the traditional trade-off in T cell therapies between longevity and potency, offering cells that not only persist longer but also retain robust anti-tumor capabilities. TIF cells demonstrate enhanced survival and can enter a reversible dormant state, like memory cells, providing long-term immunity. Without BCOR, and in combination with ZC3H12A deficiency, genes that are usually repressed might become active, enhancing both stemness- and cytotoxicity-associated genes. This could potentially remove brakes on the T cell stemness and cytotoxic programs, enhancing therapeutic efficacy.

Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear. Through a bioinformatics approach that allows integrated analyses of multiple single-nucleus transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization.

Our analyses indicated that these cell cycle-related events occur predominantly in excitatory neurons and that cellular senescence is likely their immediate terminal fate. Quantitatively, the number of cell cycle re-engaging and senescent neurons decreased during the normal brain aging process, but in the context of late-onset Alzheimer's disease (AD), these cells accumulate instead. Transcriptomic profiling of these cells suggested that disease-specific differences were predominantly tied to the early stage of the senescence process, revealing that these cells presented more proinflammatory, metabolically deregulated, and pathology-associated signatures in disease-affected brains. Similarly, these general features of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the Parkinson's disease (PD)-Lewy body dementia (LBD) model.

An extended analysis conducted in a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between the cell cycle and senescence processes in neurons in this cross-species setting.

The major risk factor for chronic disease is chronological age, and age-related chronic diseases account for the majority of deaths worldwide. Targeting senescent cells that accumulate in disease-related tissues presents a strategy to reduce disease burden and to increase healthspan. The senolytic combination of the tyrosine-kinase inhibitor dasatinib and the flavonol quercetin is frequently used in clinical trials aiming to eliminate senescent cells.

Here, our goal was to computationally identify natural senotherapeutic repurposing candidates that may substitute dasatinib based on their similarity in gene expression effects. The natural senolytic piperlongumine (a compound found in long pepper), and the natural senomorphics parthenolide, phloretin, and curcumin (found in various edible plants) were identified as potential substitutes of dasatinib. The gene expression changes underlying the repositioning highlight apoptosis-related genes and pathways. The four compounds, and in particular the top-runner piperlongumine, may be combined with quercetin to obtain natural formulas emulating the dasatinib+quercetin formula.

Atherosclerosis is the major cause of heart attacks and stroke around the world and occurs when fat deposits build up inside the arteries. Atherosclerosis can be reduced with a healthy diet or drugs called statins that slow or reverse the buildup of deposits. Previous studies had found that smooth muscle cells metamorphose into different types of cells inside these atherosclerotic plaques and multiply to make up most cells within the plaques. Yet until now, few studies had examined the cancer-like properties of the cells and if these changes contributed to atherosclerosis. To learn more, researchers closely tracked the development of transformed smooth muscle cells in mice with atherosclerosis and sampled plaques of people with atherosclerosis. They found striking parallels between changes in the smooth muscle cells and tumor cells, including hyperproliferation, resistance to cell death, and invasiveness.

DNA damage, another hallmark of cancer, accumulated in the mouse and human smooth muscle cells and appears to accelerate atherosclerosis, the researchers found. The researchers could further accelerate atherosclerosis in mice by introducing a genetic mutation that increased DNA damage within the smooth muscle cells. Vascular tissue from healthy mice and people had no signs of smooth muscle cells with the DNA damage found in atherosclerotic plaques. "The cells stay inside existing plaques, which makes us think that they behave mostly like benign tumor cells, but more work needs to be done in humans and animal models to address this hypothesis." If atherosclerosis is driven by cancer-like cells, anticancer therapies may be a potential new way to treat or prevent the disease.

Numerous studies have indicated that aged microglia are inflamed, have reduced phagocytic capacity, and have decreased motility. Microglia exhibit several hallmarks of aging that potentially contribute to their age-related dysfunction, such as shortened telomeres, altered intercellular communication, molecular alterations, and a loss of proteostasis. Furthermore, many recent studies have started to reveal the molecular changes that define microglial aging. Single cell RNA-Seq (scRNA-Seq) analyses indicate that microglia isolated from the entire brain lose homeostasis and activate inflammatory transcriptional profiles with age. Data rich studies have also revealed partial overlaps between aging microglia and those from disease models, including Alzheimer's disease.

Studies using aged plasma administration and heterochronic blood exchange demonstrate that microglia aging is in part driven by the aged systemic environment. However, the genesis of age-related dystrophic microglial phenotypes has not been extensively investigated. So, we set out to characterize the progression of age-related hippocampal microglial dysfunction, aiming to uncover intermediate states that could be intrinsic to the aging process. To do so, we undertook complementary cellular and molecular analyses of microglia across the adult lifespan and in heterochronic parabiosis - an experimental model of aging in which the circulatory systems of young adult and aged animals are joined.

In this study, we report that microglia in the adult mouse hippocampus, a brain region responsible for learning and memory and susceptible to age-related cognitive decline, advance through intermediate states that drive inflammatory activation during aging. We utilize scRNA-Seq across the adult lifespan to identify intermediate transcriptional states of microglial aging that emerge following exposure to an aged systemic environment. Functionally, we tested the role of these intermediate states using in vitro microglia approaches and an in vivo temporally controlled adult microglia-specific Tgfb1 conditional genetic knockout mouse model to demonstrate that intermediates represent checkpoints in the progression of microglia from homeostasis to inflammatory activation, with functional implications for hippocampal-dependent cognitive decline.

Oligodendrocytes (OLs) are responsible for producing myelin sheaths that wrap around cable-like parts of nerve cells called axons, much like the plastic insulation around a wire. When the protective myelin gets damaged, be it by disease or the wear and tear of age, nerve signaling gets disrupted. Depending on where the damaged nerves lead, the disruptions can affect movement, vision, thinking and so on.

Analysis of stored autopsy tissues revealed that OLs within multiple sclerosis (MS) lesions lacked an activating histone mark called H3K27ac, while expressing high levels of two other repressive histone marks H3K27me3 and H3K9me3 associated with silencing gene activity. The research team scoured a library of hundreds of small molecules known to target enzymes that could modify gene expression and influence the silenced OLs. The team determined that the compound ESI1 (epigenetic-silencing-inhibitor-1) was nearly five times more powerful than any other compounds they considered.

The compound tripled the levels of the desired H3K27ac histone mark in OLs while sharply reducing levels of the two repressive histone marks. In both aging mice and mice mimicking MS, the ESI1 treatment prompted myelin sheath production and improved lost neurological function. Testing included tracking gene activation, measuring the microscopic new myelin sheaths surrounding axons, and observing that treated mice were quicker at navigating a water maze.

Hematopoietic stem cells (HSCs) are remarkably long-lived. HSCs typically remain dormant within the bone marrow, yet they possess the ability to activate and replenish blood cells continuously, maintaining a relatively youthful profile throughout the life of an organism. A driving force of cellular aging is the accumulation of proteins that have reached the end of their useful life. With age, proteins tend to misfold, aggregate, and accumulate inside the cell, which leads to toxic stress that can disrupt cell function. Cells that frequently engage in cell division, like progenitor cells, can dispose of protein aggregates through dilution. On the other hand, long-lived HSCs, which do not divide often, face the problem of the accumulation of misfolded proteins and subsequent toxic stress. Nevertheless, HSCs remain impervious to aging. How do they do it?

Previous studies have shown that mammalian cells express hundreds of molecular chaperones, proteins that preserve or change the three-dimensional conformation of existing proteins. Cyclophilins, one of the most abundant chaperones, have been implicated in the aging process. However, how they affect cellular proteins has not previously been studied. Working with mice, the researchers first characterized the protein content of HSCs and discovered that cyclophilin A is a prevalent chaperone. Further experiments showed that the expression of cyclophilin A was significantly decreased in aged HSCs, and genetically eliminating cyclophilin A accelerated natural aging in the stem cell compartment. In contrast, reintroducing cyclophilin A into aged HSCs enhanced their function. Together, these findings support cyclophilin A as a key factor in the longevity of HSCs.

Discovered in the 1970s, circadian clocks are essential for the regulation of biological time in most cells in the human body. These internal mechanisms adjust biological processes to a 24-hour cycle, allowing the synchronisation of cellular functions with daily variations in the environment. Circadian rhythms, which are coordinated by a central clock in the brain that communicates with clocks in different peripheral tissues, influence many functions, from our sleep patterns to our ability to metabolise food.

A study on the communication between the brain and muscle confirmed that the coordination between the central and peripheral clocks is crucial for maintaining daily muscle function and preventing the premature ageing of this tissue. Restoration of the circadian rhythm reduces the loss of muscle mass and strength, thereby improving deteriorated motor functions in experimental mouse models.

The results of the study have also demonstrated that time-restricted feeding (TRF), which involves eating only in the active phase of the day, can partially replace the central clock and enhance the autonomy of the muscle clock. More relevant still is that this restoration of the circadian rhythm through TRF can mitigate muscle loss, the deterioration of metabolic and motor functions, and the loss of muscle strength in aged mice.

"It is fascinating to see how synchronisation between the brain and peripheral circadian clocks plays a critical role in skin and muscle health, while peripheral clocks alone are autonomous in carrying out the most basic tissue functions. Our study reveals that minimal interaction between only two tissue clocks (one central and the other peripheral) is needed to maintain optimal functioning of tissues like muscles and skin and to avoid their deterioration and ageing. Now, the next step is to identify the signalling factors involved in this interaction, with potential therapeutic applications in mind."

Cardiorespiratory fitness (CRF) is a physical trait that reflects the integrated function of numerous bodily systems to deliver and use oxygen to support muscle activity during sustained, rhythmic, whole-body, large muscle physical activity. CRF can be objectively measured using direct (usually by maximal exercise testing with concomitant gas exchange analysis) or indirect (exercise predicted equations) methods with a variety of maximal or submaximal protocols.

Low CRF is considered a strong chronic disease risk factor that is not routinely assessed in clinical practice. Evidence suggests that the inclusion of CRF as a clinical vital sign would enhance patient management by improving the classification of those at high risk of adverse outcomes. The evidence supporting CRF as an important risk factor has accumulated since the 1980s through large cohort studies that investigated the prospective risk of all-cause mortality and cardiovascular events associated with CRF. Research has linked CRF to the incidence of some cancers, type 2 diabetes, metabolic syndrome, stroke, and depression. Higher CRF may even improve the prognosis in those with chronic conditions such as cancer, peripheral artery disease, heart failure, and chronic kidney disease.

The objective of this study was to conduct an overview of systematic reviews with meta-analyses from cohort studies that investigated relationships between CRF and prospective health-related outcomes among adults. We identified 26 systematic reviews with meta-analysis representing over 20.9 million observations from 199 unique cohort studies. CRF had the largest risk reduction for all-cause mortality when comparing high versus low CRF (hazard ratio, HR=0.47). A dose-response relationship for every 1-metabolic equivalent of task (MET) higher level of CRF was associated with a 11%-17% reduction in all-cause mortality (HR=0.89). The certainty of the evidence across all studies ranged from very low-to-moderate according to Grading of Recommendations, Assessment, Development and Evaluations.