Fight Aging! Newsletter, August 26th 2024

Among various host-derived factors known to be involved in the regulation of commensal microbiota, immunoglobulin A (IgA), which is abundantly secreted on mucosal surfaces, is thought to play an important role. IgA is known to regulate the balance of the commensal microbiota by binding to bacteria and contributing to the promotion or elimination of bacterial colony formation, depending on the type of bacteria. Notably, dysbiosis of the gut microbiota stemming from IgA deficiency has been observed in both human and murine models, with implications for the development of autoimmune disorders through aberrant immune activation. IgA is secreted not only in the intestinal tract but also in other mucosal sites such as the oral cavity. While there is already evidence suggesting the involvement of IgA in the regulation of oral microbiota, the impact of IgA on age-related changes in oral microbiota and its mechanisms remain unclear.

Senescent cells also cause senescence-associated secretory phenotypes (SASP), in which the cells secrete a variety of pro-inflammatory factors into the extracellular fluid. Therefore, the accumulation of senescence-like cells, which is often seen with aging and/or obesity, ultimately leads to harmful side effects. Moreover, our recent studies have shown that age-associated cellular senescence of ileal germinal center (GC) B cells induced by commensal bacteria reduces IgA production and diversity, leading to gut dysbiosis. Based on these findings, we considered the possibility that similar mechanisms may operate in the oral immune system, contributing to abnormalities in the oral microbiota with aging.

Examination of p16-luc mice, wherein the expression of the senescent cell marker p16INK4a can be visualized, raised under specific pathogen-free (SPF) or germ-free (GF) conditions, indicated that, unlike ileal germinal center (GC) B cells, the accumulation of senescent cells in GC B cells of cervical lymph nodes increases with age regardless of the presence of commensal bacteria. Furthermore, longitudinal studies utilizing the same individual mice throughout their lifespan revealed concurrent age-related alterations in the composition of the oral microbiota and a decline in salivary IgA secretion. Further investigation unveiled that B cell senescence leads to reduced IgA secretion and alteration of the oral microbiota. These findings advance our understanding of the mechanism of age-associated changes in the oral microbiota and open up possibilities of their control.

Beyond its connection to aging, senescence has been recognized as a hallmark of cancer. Whether senescence is beneficial or detrimental to cancer initiation, progression, and/or treatment has remained controversial over the past few decades. On one hand, the induction of senescence can serve as a barrier against malignant transformation and excessive hyperproliferation due to reduced proliferative capacity. On the other, SnC accumulation may act as a driver of cancer progression and therapy resistance, primarily mediated by inflammatory factors in the senescence-associated secretory phenotype (SASP). Persistent senescence has been associated with promoting malignant transformation, accelerating tumor growth, inducing cancer stemness, facilitating distant metastasis, maintaining chronic inflammation, and dampening the anti-tumor immune response.

Confirming these deleterious effects, genetic elimination of senescent cells (SnCs) was shown to delay spontaneous tumorigenesis and decrease cancer-related mortality. Senolytic agents, drugs that selectively eliminate SnCs, have also demonstrated significant potential in improving cancer therapies. Nonetheless, our studies have identified opposing, apparently beneficial, effects of therapy induced senescence (TIS), where SnCs may serve as a vaccine to drive an adaptive immune response to inhibit tumor growth and boost radiation therapy. This work is built on pioneering studies revealing innate and adaptive immune recognition of SnCs leading to their elimination and tumor suppression, often described as senescence surveillance.

Over the past decade, a growing literature has appeared that further defines roles for host immunity in mediating the anti-tumor effects of SnCs, as reflected in recent reviews. Multiple studies have implicated the upregulation of inflammatory mediators including damage-associated molecular patterns (DAMPs), chemotactic factors and other cytokines, and antigen presentation machinery in the activation of both innate and adaptive immune responses, not only driving SnC elimination via immune surveillance but also potentiating broader immune responses. Such findings highlight the positive aspects of TIS, extending beyond growth suppression to significantly enhance anti-tumor immunity.

A factor underlying the apparent inconsistency may be that SnCs, including those formed by cancer therapies, can express immune checkpoint ligands that allow SnCs to evade surveillance and protect their microenvironment. Thereby, some benefits of immune checkpoint blockade (ICB) therapy in combination with genotoxic or targeted therapies may be mediated by overcoming immunosuppression driven by TIS and restoring immune surveillance.

This review examines cellular senescence in the context of cancer, highlighting the diverse roles of SnCs in the tumor microenvironment (TME) and arguing for a broad view of senescence and its functions. We will discuss how the interaction between SnCs and the immune system can lead to either beneficial or detrimental outcomes depending on the specific features of SnCs, particularly the SASP. We will then review SASP modulation and SnC elimination via senolytics. Such approaches may limit the adverse effects of senescence while amplifying its beneficial impact, which ultimately presents an alternative strategy to improve cancer therapies.

This review aimed to provide a brief summary of the effects of aging on cardiovascular disease through the accumulation of senescence, highlighting the crucial involvement of vascular cells in the progression of atherosclerosis and other cardiovascular diseases (CVDs). We also sought to describe the potential of senolytics to improve vascular function and reduce CVD in aging. Endothelial dysfunction occurs with aging and promotes reductions in nitric oxide (NO), increases in reactive oxygen species (ROS), a proinflammatory phenotype, and is associated with an increase in senescent cell accumulation. Understanding how endothelial cell (EC) senescence influences endothelial dysfunction, atherosclerosis, and CVD is important in the design of novel effective therapeutics.

EC senescence is recognized as a contributing factor to endothelial dysfunction and is a major step in the development of atherosclerosis and other CVDs. Evidence suggests that genetic or pharmacological elimination of senescence, specifically in ECs, can attenuate vascular dysfunction and disease in aging through a reduction in the milieu of senescence-associated secretory phenotype (SASP) factors present in senescence. These findings have also improved our understanding of the endothelium's response to aging and how to combat endothelial dysfunction in this setting. Specifically, targeting endothelial cell senescence appears to be a promising strategy for maintaining endothelial functions and improving vascular health.

Preclinical evidence has shown the potential of senolytics for the treatment and prevention of CVD, leading to the investigation of senolytic therapy in the clinical setting. In a preliminary clinical trial investigating the effectiveness of senolytics, a treatment regimen involving a 3-day administration of dasatinib and quecertin (D&Q) per week for 3 weeks was implemented. This study was conducted on 14 patients with idiopathic pulmonary fibrosis and demonstrated high retention and completion rates, indicating the safety of this treatment. Although there were no significant improvements in pulmonary function, treatment with D&Q led to notable improvements in physical function, as evidenced by increases in 6-min walk distance and 4-min gait speed. Moreover, correlations were observed between enhanced physical function and a reduction in SASP factors.

Additionally, preliminary data from a phase 1 clinical trial involving patients with diabetic kidney disease revealed that senolytic therapy with D&Q reduced senescence burden in both adipose and epidermis tissue. This reduction was associated with a decrease in circulating cytokines and matrix metalloproteinases. In a 12-week pilot study of D&Q treatment on individuals with early-stage Alzheimer's disease (AD), there was no significant difference between neuroimaging endpoints and cognitive function. However, results indicated a reduction in cytokine and chemokine levels associated with senescence as well as a trending increase in Aβ42, a biomarker that is inversely related to Alzheimer's disease diagnosis. These studies show promise for the therapeutic potential of senolytic therapy in eliminating senescence, relieving SASP accumulation, and reducing inflammation, although more compounds with appropriate safety, tolerability, and feasibility need to be developed and investigated. Moreover, clinical trials using senolytic therapy in the context of atherosclerosis and cardiovascular disease should be conducted.

Currently, there is not enough research on the use and treatment of senolytic therapy in cardiovascular diseases in the clinical setting. It is unclear if senescent cell clearance, either systemically or in a cell-specific manner, will impact the cardiovascular system, specifically on health span in general. Furthermore, the long-term effects of senescent cell elimination, both systemic and tissue-specific, are not well known. More research must be conducted to answer these questions. While short-term clearance of senescent endothelial and vascular smooth muscle cells improved cardiovascular function and atherosclerosis in preclinical models, further studies are necessary to ensure that the elimination of this cell population has no adverse effects on systemic function, both long-term and short-term. Nevertheless, the potential of senolytics to transform age-related cardiovascular diseases and improve health span is an exciting frontier.

The researchers found the protein - called DdrC (for DNA Damage Repair Protein C) - in a fairly common bacterium called Deinococcus radiodurans (D. radiodurans), which has the decidedly uncommon ability to survive conditions that damage DNA - for example, 5,000 to 10,000 times the radiation that would kill a regular human cell. DdrC scans for breaks along the DNA and when it detects one it snaps shut - like a mousetrap. This trapping action has two key functions: "It neutralizes it (the DNA damage), and prevents the break from getting damaged further. And it acts like a little molecular beacon. It tells the cell 'Hey, over here. There's damage. Come fix it.'"

Typically proteins form complicated networks that enable them to carry out a function. DdrC appears to be something of an outlier, in that it performs its function all on its own, without the need for other proteins. The team was curious whether the protein might function as a "plug-in" for other DNA repair systems. They tested this by adding it to a different bacterium: E. coli. "To our huge surprise, it actually made the bacterium over 40 times more resistant to UV radiation damage. This seems to be a rare example where you have one protein and it really is like a standalone machine."

In theory, this gene could be introduced into any organism - plants, animals, humans - and it should increase the DNA repair efficiency of that organism's cells. "The ability to rearrange and edit and manipulate DNA in specific ways is the holy grail in biotechnology. What if you had a scanning system such as DdrC which patrolled your cells and neutralized damage when it happened? This might form the basis of a potential cancer vaccine."

The bacterium Deinococcus radiodurans is known to survive high doses of DNA damaging agents. This resistance is the result of robust antioxidant systems which protect efficient DNA repair mechanisms that are unique to Deinococcus species. The protein DdrC has been identified as an important component of this repair machinery. DdrC is known to bind to DNA in vitro and has been shown to circularize and compact DNA fragments. The mechanism and biological relevance of this activity is poorly understood.

Here, we show that the DdrC homodimer is a lesion-sensing protein that binds to two single-strand (ss) or double-strand (ds) breaks. The immobilization of DNA breaks in pairs consequently leads to the circularization of linear DNA and the compaction of nicked DNA. The degree of compaction is directly proportional with the number of available nicks. Previously, the structure of the DdrC homodimer was solved in an unusual asymmetric conformation. Here, we solve the structure of DdrC under different crystallographic environments and confirm that the asymmetry is an endogenous feature of DdrC. We propose a dynamic structural mechanism where the asymmetry is necessary to trap a pair of lesions. We support this model with mutant disruption and computational modeling experiments.

Alzheimer's, Parkinson's, and other neurological disorders can be seen as "dirty brain" diseases, where the brain struggles to clear out harmful waste. Aging is a key risk factor because, as we grow older, our brain's ability to remove toxic buildup slows down. However, new research in mice demonstrates that it's possible to reverse age-related effects and restore the brain's waste-clearing process.

Once laden with protein waste, cerebrospinal fluid (CSF) in the skull needs to make its way to the lymphatic system and, ultimately, to the kidneys, where it is processed along with the body's other waste. The new research combines advanced imaging and particle-tracking techniques to describe for the first time in detail the route by way of the cervical lymph vessels in the neck through which half of dirty CSF exits the brain.

Unlike the cardiovascular system, which has one big pump - the heart - fluid in the lymphatic system is instead transported by a network of tiny pumps. These microscopic pumps, called lymphangions, have valves to prevent backflow and are strung together, one after another, to form lymph vessels. The researchers found that as the mice aged, the frequency of contractions decreased, and the valves failed. As a result, the speed of dirty CSF flowing out of the brains of older mice was 63 percent slower compared to younger animals.

The team then set out to see if they could revive the lymphangions and identified a drug called prostaglandin F2α, a hormone-like compound commonly used medically to induce labor and known to aid smooth muscle contraction. The lymphangions are lined with smooth muscle cells, and when the researchers applied the drug to the cervical lymph vessels in older mice, the frequency of contractions and the flow of dirty CSF from the brain both increased, returning to a level of efficiency found in younger mice.

Cervical lymphatic vessels (cLVs) have been shown to drain solutes and cerebrospinal fluid (CSF) from the brain. However, their hydrodynamical properties have never been evaluated in vivo. Here, we developed two-photon optical imaging with particle tracking in vivo of CSF tracers (2P-OPTIC) in superficial and deep cLVs of mice, characterizing their flow and showing that the major driver is intrinsic pumping by contraction of the lymphatic vessel wall.

Contraction frequency and flow velocity were reduced in aged mice, which coincided with a reduction in smooth muscle actin expression. Slowed flow in aged mice was rescued using topical application of prostaglandin F2α, a prostanoid that increases smooth muscle contractility, which restored lymphatic function in aged mice and enhanced central nervous system clearance. We show that cLVs are important regulators of CSF drainage and that restoring their function is an effective therapy for improving clearance in aging.

A general cause of cellular senescence and organism aging is the progressive accumulation of dysfunctional organelles and cellular damage. Impairment of proteostasis alters the protein quality control systems, leading to the accumulation of aberrant and dysfunctional macromolecules and is considered among the primary hallmarks of aging. All cells take advantage of an array of mechanisms to preserve the stability and functionality of their proteins or to remove them when they are irreversibly damaged. One of the most important cellular housekeeping and prosurvival pathways is macroautophagy, hereafter named autophagy, whose main action is to remove damaged proteins/organelles and generate molecules that sustain cellular core metabolism.

To identify uncharacterized factors that control aging and proteostasis, we screened our published transcriptomic profiles. We discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the orthologous myt-1 gene in C. elegans dramatically shortened life span and decreased animal survival upon exposure to oxidative stress. We tested the long-lived glp-1 (which shows reduced proliferation of germline cells) and eat-2 (a genetic dietary restriction model) mutants. The findings that the absence of myt-1 completely blunted the life extension of glp-1 mutants and partially affected the longevity of eat-2 mutants suggest that myt-1 is mediating the response to germline signals and dietary cues, respectively.

Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy aging.

To study possible determinants of longevity in a cohort of middle-aged men followed for 61 years until extinction using measurements taken at baseline and at years 31 or 61 of follow-up. In 1960, two rural cohorts including a total of 1712 men aged 40-59 years were enrolled within the Italian section of the Seven Countries Study of Cardiovascular Diseases, and measurements related to mainly cardiovascular risk factors, lifestyle behaviors, and chronic diseases were taken at year 0 and year 31 of follow-up (when only 390 could be examined). Multiple linear regression models were computed to relate personal characteristics with the length of survival in both dead men and survivors.

Baseline cardiovascular risk factors, smoking and dietary habits, and chronic diseases (taken at year 0 with men aged 40-59 years) were significant predictors of the length of survival both from year 0 to year 31 and from year 0 to year 61, but only chronic diseases were independent predictors for the period of 31 to 61 years. Significant predictors of survival using measurements taken at year 31 (age range 71 to 90 years) were only smoking and dietary habits and chronic diseases. In conclusion, during a lifetime of follow-up, the personal characteristics with continuous predictive power of survival were only lifestyle behaviors and major chronic diseases.

A new type of degenerative brain disease, limbic-predominant age-related TDP-43 encephalopathy (LATE), was recognised just a decade or so ago, and remains relatively unknown. In the disease, the TDP-43 protein accumulates particularly in the limbic brain regions, which are also affected in the early stages of Alzheimer's disease. Accordingly, symptoms of LATE are similar to those of early Alzheimer's, but typically progress more slowly and are milder.

Researchers conducted the first study exploring the prevalence of LATE in a population-based Finnish autopsy dataset encompassing 300 Finns over the age of 85. LATE was found to be very common. Changes associated with the disease were identified in at least every second individual over the age of 85. The association between LATE and dementia was independent of other brain changes found in the study subjects. "The results suggest that LATE is, alongside Alzheimer's, one of the strongest determinants of dementia in the oldest old."

Parkinson's disease (PD) is an age-related movement disorder caused by the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) of the midbrain, however, the underlying causes of this DA neuron loss in PD is unknown and there are currently no effective treatment options to prevent or slow neuronal loss or the progression of related symptoms. It has been shown that both environmental factors as well as genetic predispositions underpin PD development and recent research has revealed that lysosomal dysfunction and lipid accumulation are contributors to disease progression, where an age-related aggregation of alpha-synuclein as well as lipids have been found in PD patients.

We have recently discovered that artificial induction of lipid accumulation leads to cellular senescence of DA neurons, suggesting that lipid aggregation plays a crucial role in the pathology of PD by driving senescence in these vulnerable DA neurons. We propose that the expression of a cellular senescence phenotype in the most vulnerable neurons in PD can be triggered by lysosomal impairment and lipid aggregation. Importantly, we highlight additional data that perilipin (PLIN2) is significantly upregulated in senescent DA neurons, suggesting an overall enrichment of lipid droplets (LDs) in these cells.

These findings align with our previous results in dopaminergic neurons in highlighting a central role for lipid accumulation in the senescence of DA neurons. Importantly, general lipid droplet aggregation and global lysosomal impairment have been implicated in many neurodegenerative diseases including PD. Taken together, our data suggest a connection between age-related lysosomal impairment, lipid accumulation, and cellular senescence in DA neurons that in turn drives inflammaging in the midbrain and ultimately leads to neurodegeneration and PD.

Arterial stiffness, a recognized marker of vascular health, reflects the elasticity and compliance of arteries. Central arterial stiffness, as measured by pulse wave velocity, is a predictor of cardiovascular events and mortality independent of traditional risk factors. Arterial stiffness is multifaceted, comprised of both active and passive stiffness. Aging is associated with increased arterial stiffness, caused by changes in active and passive arterial stiffness.

The active contribution to arterial stiffness, otherwise known as vascular tone, is regulated by vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). ECs, lining the inner surface of blood vessels, contribute towards vascular tone by releasing bioactive molecules that modulate vasoconstriction and vasodilation of VSMCs. Nitric oxide (NO), a key endothelium-derived vasodilator, is crucial for maintaining proper vessel function. EC dysfunction leads to impaired NO production, contributing towards augmented vasoconstriction, oxidative stress, and ultimately, cardiovascular diseases.

Passive stiffness encompasses extracellular matrix (ECM) structural proteins. Collagen and elastin are important structural proteins in ECM, contributing to mechanical properties of blood vessels. Collagen provides tensile strength, while elastin confers elasticity. The balanced interaction between collagen and elastin is vital for maintaining arterial integrity, allowing blood vessels to withstand mechanical stress. Arterial tissues from different anatomical regions on the aorta exhibit distinct mechanical properties and endothelial responses due to variations in structure, hemodynamics, and local microenvironments.

In young and healthy individuals, damaged cells can enter a state of cellular senescence, which limits the spread of dysfunctional cells. These senescent cells produce a senescence-associated secretory phenotype (SASP) which attracts immune cells that may ultimately clear these senescent cells. Recent studies suggest that when the immune cells themselves become senescent, they fail to clear other senescent cells and drive senescence, and age-related dysfunction of other organs.

As we age, T cells may develop cellular senescence, similar to fibroblasts and other cell types in which the state of cellular senescence has been extensively investigated. But importantly, the cell surface markers frequently used to detect immunosenescent T cells, such as the loss of CD27 and CD28 expression or the upregulated KLRG-1 or Leu7 expression, or the exhaustion marker PD-1, do not accurately demarcate the population that is in a true state of senescence. Rather, they mark a heterogenous population of T cells, mostly but not exclusively consisting of senescent cells. Referring to this population as senescent T cells is, at best, an oversimplification and leads to a significant underestimation and misinterpretation of the actual number of senescent T cells in individual patients. Several hallmarks of cellular senescence, such as p16, p21, absence of proliferation, DNA-SCARS, telomere-associated foci (TAFs), senescence-associated heterochromatin foci (SAHFs), loss of LMNB1 and increased senescence-associated β-gal activity, should be included to accurately measure senescent T cells.

Future studies should investigate the functional properties of T cells that are in a state of cellular senescence in the different T cell differentiation stages. For a long time, research into T cell senescence has focused on late-stage differentiation stages, such as the CD28null population, the CD57+ TEMRA cells (the effector memory cells that re-express CD45RA), or the exhausted T cells. The question now arises whether earlier T cell differentiation stages can also become senescent. Knowledge on the functional consequences of accumulating senescent naïve or central memory T cells is lacking. It is essential to determine whether these subpopulations of senescent T cells increase in age-related diseases and actively contribute to pathology. Additionally, it is important to explore whether they secrete a SASP and how they differ functionally from non-senescent T cells of the same differentiation stage. These are critical open questions that require further investigation.

Suppose you were to take a group of people who were on the back end of current lifespans and give them an experimental drug to boost their muscle mass. Like most older people, they have lost a significant amount of the muscle they carried in midlife. By giving them our experimental muscle-building drug, we're hoping to restore their function, keeping them out of the nursing home and playing with their grandchildren. Excitingly, the drug seems to work. Over the course of a few months, the volunteers in our trial who receive our drug put on muscle mass, while people receiving the placebo continue to lose muscle. Mission accomplished, right?

Yet when the researchers test the volunteers on standardized tests of muscle strength and function, the newly-muscular elders are no stronger than when the trial started, and no better off than the people who were taking sugar pills. What's the drug? Actually, it's a lot of drugs. People have been trying to develop therapies to help aging people regain muscle mass and strength for decades now, and while a number of them have bulked up subjects' biceps, they have consistently failed to deliver on the functional outcomes that matter most.

As with other age-related diseases and disabilities, sarcopenia is a complex condition, driven by the collateral damage inflicted on multiple cellular and molecular structures by the processes that keep us alive. As these structural units are damaged or destroyed, we lose functional contribution to delivering muscle strength and power. To reverse this degenerative process, it isn't enough to simply add more of the dysfunctional muscle tissue aging people have. Instead, we need to develop rejuvenation biotechnologies capable of removing and repairing the range of cell and tissue damage that robs our muscles of their strength.

Aging is a complex process associated with nearly all diseases. Understanding the molecular changes underlying aging and identifying therapeutic targets for aging-related diseases are crucial for increasing healthspan. Although many studies have explored linear changes during aging, the prevalence of aging-related diseases and mortality risk accelerates after specific time points, indicating the importance of studying nonlinear molecular changes.

In this study, we performed comprehensive multi-omics profiling on a longitudinal human cohort of 108 participants, aged between 25 years and 75 years. The participants resided in California, United States, and were tracked for a median period of 1.7 years, with a maximum follow-up duration of 6.8 years. The analysis revealed consistent nonlinear patterns in molecular markers of aging, with substantial dysregulation occurring at two major periods occurring at approximately 44 years and 60 years of chronological age. Distinct molecules and functional pathways associated with these periods were also identified, such as immune regulation and carbohydrate metabolism that shifted during the 60-year transition and cardiovascular disease, lipid metabolism, and alcohol metabolism changes at the 40-year transition.

Overall, this research demonstrates that functions and risks of aging-related diseases change nonlinearly across the human lifespan and provides insights into the molecular and biological pathways involved in these changes.

In the brains of those who suffer from Alzheimer's, amyloids accumulate and build up into sticky plaque that disrupts brain functions and causes cognitive decline. The big unknown has been exactly how that occurs. According to the most widely adopted hypothesis, the amyloid beta buildup disrupts cell-to-cell communication and activates immune cells in a process that eventually destroys brain cells.

Researchers now present a new hypothesis, emphasizing a different role for amyloid beta, a simple protein that forms in all brains but normally dissolves out by natural processes. In experiments, they used cutting-edge analytical technologies to identify and measure the level of more than 8,000 proteins in human brains with Alzheimer's, as well as similar proteins in mice. Focusing on proteins whose levels increased most dramatically, they identified more than 20 proteins that co-accumulate with amyloid beta in both the human brains with Alzheimer's and the mice. As the research continues, they suspect they'll find more.

"Once we identified these new proteins, we wanted to know whether they were merely markers of Alzheimer's or if they could actually alter the disease's deadly pathology. To answer that, we focused on two proteins, midkine and pleiotrophin. Our research showed they accelerated amyloid aggregation both in the test tube and in mice. In other words, these additional proteins may play an important role in the process that leads to brain damage rather than the amyloid itself. This suggests they might be a basis for new therapies for this terrible brain affliction that's been frustratingly resistant to treatment over the years."

Adult cardiomyocytes in humans are terminally differentiated, i.e., they are post-mitotic/rarely dividing. Thus, telomere shortening/attrition due to repetitive cell division, a major mechanism of senescence in proliferating cells, termed replicative senescence, may not occur in cardiomyocytes. However, length-independent telomere damage, which may be caused by reactive oxygen species (ROS), induces senescence in terminally differentiated cardiomyocytes. Accumulating lines of evidence suggest that cardiomyocytes develop senescence during aging and in response to stresses such as ischemia/reperfusion and myocardial infarction (MI). β-adrenergic receptor stimulation and inflammation may also contribute to cardiomyocyte senescence during aging.

Senescent cardiomyocytes exhibit features of senescence commonly seen in other cell types, including enlarged cell size, DNA damage responses, senescence-associated β-galactosidase (SA-β-gal) activity, and the senescence-associated secretory phenotype (SASP). It should be noted that senescent cells are highly heterogeneous and their properties are dynamically altered. Thus, senescent cardiomyocytes may consist of multiple cell populations with distinct features. Furthermore, senescent cells in the heart can be either beneficial or detrimental depending on the cell types and conditions in which they are induced. Senescence in cardiac fibroblasts and endothelial cells may affect the heart differently from that in cardiomyocytes. Thus, conducting a deeper characterization of the gene expression profile in senescent cardiomyocytes and other cell types in the heart at the single-cell level is important.

There is a great interest in finding strategies to specifically eliminate senescent cells but not non-senescent cells, i.e., senolysis. Growing evidence supports the rationale of senolysis and its anti-aging effects. Since aging is a major risk factor for heart disease, senolysis could represent a promising intervention for the heart with senescent cardiomyocytes. Senolysis can be achieved using senolytic drugs (such as Navitoclax or Dasatinib and Quercetin), pharmacogenetic approaches (including the INK-ATTAC model), and immunogenetic interventions (CAR T cells or senolytic vaccination). Importantly, unlike regenerative and proliferative cells, cardiomyocytes are terminally differentiated. Thus, cardiomyocytes may not be replenished after senolysis. This raises the question of whether senolysis improves cardiac function despite the loss of cardiomyocytes. Although there have been reports suggesting that removal of cardiomyocytes by senolytics has salutary effects, thorough investigation into the mechanisms of cardiomyocyte senescence, especially the mechanisms through which cardiomyocytes develop and maintain the senescent state, is critical to identify or develop strategies for "safe" senolysis.