Senolytic Drugs and Aerobic Exercise Each Rejuvenate the Aging Mouse Heart

The aging heart is a quiet battleground. Over decades, its muscle cells accumulate molecular wear, stiffen, and lose the coordinated rhythm of contraction and relaxation that keeps blood moving efficiently through the body. A new study published in Aging Cell suggests that two very different interventions—a drug cocktail designed to kill worn-out cells and a modest regimen of treadmill running—can each slow this decline in mice, offering some of the clearest evidence yet that the burden of cellular senescence in the heart is not an inevitable consequence of growing old.

Cellular senescence is a state in which cells permanently stop dividing but refuse to die. First described in 1961 by Leonard Hayflick and Paul Moorhead, senescence was once viewed as a simple safeguard against cancer. Scientists now understand it as a far more complex condition: senescent cells suffer mitochondrial dysfunction, oxidative stress, and DNA damage, and they secrete a potent cocktail of inflammatory and fibrotic molecules known as the senescence-associated secretory phenotype, or SASP. Factors such as interleukin-6, tumor necrosis factor alpha, and transforming growth factor beta can spread inflammation and even push neighboring cells into senescence themselves, creating a self-amplifying cycle of tissue deterioration.

In the heart, this matters enormously. Senescent cardiomyocytes—the contractile muscle cells—show impaired shortening, defective calcium handling, and resistance to apoptosis through pro-survival pathways. Senescent fibroblasts and endothelial cells contribute to fibrosis and maladaptive remodeling. Together, these changes stiffen the left ventricle, impair its relaxation, and set the stage for heart failure, particularly the diastolic form in which the heart fills poorly despite pumping adequately. Prior work had shown that senolytic drugs such as dasatinib plus quercetin, or the BCL-family inhibitor navitoclax, could clear senescent cardiac cells when given to already-aged mice, but the chronic, preventive effects of these drugs on the heart remained largely unexplored.

The research team, based at McMaster University, set out to close that gap with an unusually long experiment. They began treating twelve-month-old mice—roughly early middle age in mouse terms—with one of four regimens for nine months: a vehicle control, biweekly oral doses of dasatinib plus quercetin, twice-weekly treadmill exercise sessions, or both interventions combined. By the end of the study, the animals had reached twenty-one months of age, the threshold of old age. A separate cohort of four-month-old young mice served as a healthy benchmark. Crucially, both male and female mice were included, and the investigators reported no significant sex differences in any outcome.

The functional results were striking. Using high-frequency ultrasound, the researchers measured how quickly the left ventricle relaxed between beats—the isovolumetric relaxation time—and combined contraction and relaxation measures into the myocardial performance index, a sensitive gauge of overall cardiac health. Naturally aged control mice showed relaxation times roughly 40 percent longer and performance indices about 44 percent higher than the best-performing treatment groups, indicating substantially worse myocardial function. Exercise-treated mice also displayed a markedly better E/A ratio, a frontline marker of diastolic filling, suggesting that aerobic training preserved the ventricle’s ability to relax and fill with blood. Notably, systolic measures such as ejection fraction were largely preserved across all aged groups, reinforcing the growing view that diastolic decline, not systolic failure, is the dominant functional signature of the aging heart.

Beneath those functional improvements lay a cellular story. Using immunofluorescence to detect the canonical senescence markers p16, p21, and gamma-H2AX—a marker of DNA damage—the team counted labeled cardiomyocytes and interstitial cells across four regions of each heart. Exercise reduced p16-positive cardiomyocytes by 29 percent, senolytics by 21 percent, and the combination by 27 percent compared with aged controls. Similar reductions appeared for p21, with exercise cutting positive cardiomyocytes by nearly half, and for gamma-H2AX, where the combined intervention lowered DNA-damage-positive cells by 36 percent. Interstitial cells followed the same pattern. The researchers also found that p21 expression was highest in the central left ventricle and lower at its anterior and posterior edges, revealing a spatial heterogeneity in cardiac senescence that whole-tissue analyses can easily miss.

Perhaps the most compelling finding was correlational: across all animals, the abundance of p16- and p21-positive cells tracked closely with worse cardiac function. Higher marker levels were associated with longer relaxation times, higher myocardial performance indices, and lower cardiac output and stroke volume, with correlation coefficients reaching 0.53. Marker expression was also coordinated across cell types—p21-positive cardiomyocytes and interstitial cells correlated with a striking r of 0.91—suggesting that senescence in the aging myocardium behaves as a tissue-wide phenomenon rather than a collection of isolated bad cells. This statistical link between senescent burden and functional decline strengthens the causal plausibility of the interventions, even though correlation alone cannot prove mechanism.

The study was not without surprises. At the whole-heart level, neither exercise nor senolytics significantly reduced p16 or p21 protein expression, and mRNA results were inconsistent, with the combined group paradoxically showing elevated p53 gene expression. Canonical SASP factors measured in heart tissue and serum—using western blotting, quantitative PCR, and the sensitive Olink proteomics panel—showed no differences between young, aged, and treated animals. The authors suggest several explanations: whole-heart lysates dilute cell-specific signals, twenty-one months may be too early for a pronounced SASP surge, and cardiac cells may secrete atypical SASP profiles dominated by fibrotic and hypertrophic factors rather than classic inflammatory cytokines. The disconnect between cellular and whole-tissue measurements is itself informative, indicating that senolytic and exercise effects are most visible at the single-cell level during early old age.

Equally notable was what did not happen: combining the interventions produced no additive benefit. Exercise and senolytics each worked about as well alone as together, contradicting the researchers’ initial hypothesis. One possibility is that both interventions converge on the same downstream targets—the p16, p21, and p53 pathways and inflammatory signaling—so that once senescent cell clearance reaches a ceiling, adding a second tool yields diminishing returns. Another is that at twenty-one months, the pool of senescent cells is still moderate; exercise during the off-weeks of the intermittent senolytic schedule may have already depleted the cells that dasatinib and quercetin would otherwise have cleared. The timing of treatment relative to senescence accumulation may therefore be decisive, and the authors caution that early senolytic use could theoretically remove cardiomyocytes from a tissue with minimal regenerative capacity.

The broader implications are tantalizing. This is the first demonstration that aerobic exercise can act as a natural senolytic in the aging heart, extending earlier findings in skeletal muscle and in young animals. It is also the longest senolytic intervention yet tested in cardiac tissue, showing that preventive, rather than rescue, administration of dasatinib plus quercetin can limit senescent cell accumulation over most of a mouse’s adult life. For a rapidly aging human population facing rising rates of heart failure with preserved ejection fraction, the message is doubly appealing: one intervention is already available in every gym, while the other is advancing through the emerging field of geroscience. The authors emphasize that long-term efficacy, optimal dosing, and systemic effects must be validated before clinical translation, but the vision of preserving cardiac function by targeting the cellular biology of aging itself has moved a meaningful step closer to reality.

Subject of Research: Effects of chronic senolytic treatment and aerobic exercise on cellular senescence and myocardial function in the aging mouse heart

Article Title: Chronic Senolytic Treatment and/or Aerobic Exercise Reduce Senescence and Improve Myocardial Function During Aging in the Heart

Article References: Bevington, R. T., Johnson, A. L., Hockey, B. L., Fajardo, V. A., & Parise, G. (2026). Chronic Senolytic Treatment and/or Aerobic Exercise Reduce Senescence and Improve Myocardial Function During Aging in the Heart. Aging Cell, 25(10), Article e70759. https://doi.org/10.1111/acel.70759

Image Credits: AI Generated

DOI: 10.1111/acel.70759

Keywords: cellular senescence, senolytics, dasatinib, quercetin, aerobic exercise, aging heart, myocardial function, cardiomyocytes, SASP, diastolic function, p16, p21