Age is a major risk factor for heart failure, but one that has been historically viewed as non-modifiable. Emerging evidence suggests that the biology of aging is malleable, and can potentially be intervened upon to treat age-associated chronic diseases, such as heart failure. While aging biology represents a new frontier for therapeutic target discovery in heart failure, the challenges of translating Geroscience research to the clinic are multifold. In this review, we propose a strategy that prioritizes initial target discovery in human biology. We review the rationale for starting with human omics, which has generated important insights into the shared (patho)biology of human aging and heart failure. We then discuss how this knowledge can be leveraged to identify the mechanisms of aging biology most relevant to heart failure. Lastly, we provide examples of how this human-first Geroscience approach, when paired with rigorous functional assessments in preclinical models, is leading to early-stage clinical development of gerotherapeutic approaches for heart failure.

Aging leads to structural and functional deterioration of the heart, reducing its capacity to withstand internal and external stressors and consequently increasing the risk of heart failure. Exercise is a potent modulator of cardiovascular and metabolic health, offering numerous physiological benefits that can persist throughout the aging process. Studies suggest that exercise can decelerate age-related cardiac deterioration and mitigate the risk of heart failure. In this review, we discuss recent advances in our understanding of exercise-mediated molecular and cellular adaptations that could serve as therapeutic targets for age-related cardiac remodeling and functional decline. We also explore how exercise-induced changes may enhance cardiac resilience with age, examine sex differences in cardiac aging and response to exercise, and highlight the value of murine exercise models as research tools for identifying novel therapeutic targets and strategies to combat heart failure.

With the increase in life expectancy globally, the challenge of dealing with aging becomes more prominent. Aging is a risk factor for several diseases, including cardiovascular disease. Mitochondria, which have long been studied in relation to aging, play a crucial role in maintaining cellular homeostasis. However, there is a limitation in interorganellar communication as organisms age. The unfolded protein response in mitochondria (UPR^mt) is activated during stress to maintain mitochondrial homeostasis and prevent the accumulation of damaged mitochondria. This response involves signaling from the mitochondria to the nucleus, leading to transcriptional changes. In the context of aging heart, this review explores the role of mitochondria in terms of function and morphology. It also discusses the impact of UPR^mt on cardiac diseases such as heart failure, acute myocardial infarction, and dilated cardiomyopathy. The review also highlights the potential role of mitochondria-endoplasmic reticulum contact sites (MERCs) in modulating UPR^mt during aging. Finally, it provides an update on molecules that induce UPR^mt activity, potentially benefiting the aging heart with cardiac disease.

Introduction: Aging is a multifaceted biological process characterized by a progressive decline in cellular and tissue function. It significantly impacts the cardiovascular system and contributes to the onset of cardiovascular diseases. The mitochondria (mt) and the endoplasmic reticulum (ER) play synergistic roles in maintaining cellular homeostasis and energy production in the heart. Nevertheless, their response to cardiac aging is not well known.

Aim: This study explores mt and ER stress responses and their associated factors, such as metabolic, cellular, and autophagic stress, in cardiac aging.

Methods and Results: We utilized 10- and 25-month-old CBA/CaJ mice to evaluate mt, ER, and their associated factors, such as metabolic, cellular, and autophagic stress responses. We studied the gene expression for mitochondrial biogenesis, mt and ER stress response, autophagy and metabolic markers, and activating transcription factors that mediate cellular stress responses. We found no significant difference in mtDNA content and the mRNA expression of the mt transcription factor, Tfam; however, selective mtDNA genes, such as mt-Cytb and mt-Co2, showed significant induction in 25-month-aged compared to 10-month-young hearts. Interestingly, genes of several mitochondrial stress response proteases and their components, including Lonp1, Yme1l1, Afg3l2, and Spg7, were significantly induced, with a substantial induction of Clpp and Clpx. However, age-associated differences were not observed in the induction of mt chaperones (Hspa9 and Hspd1), but significant induction of Dnaja2, a mitochondrial co-chaperone, was observed. The ER stress transcription factors Xbp1 and Atf6 were markedly induced in aged hearts, accompanied by decreased expression of ER stress chaperone Hsp90b with no change in Hspa5 and Dnajb9 chaperones. However, induction of Dnm1l was significant, whereas Mfn1 and Fis1 were downregulated in contrast to Mfn2, suggesting dysregulated mitochondrial dynamics in the aged heart with no change in autophagy and metabolic stress regulators observed. Furthermore, aged hearts showed significantly increased oxidative damage as evidenced by elevated lipid peroxidation (4-HNE) levels.

Conclusion: These findings demonstrate that aging triggers mt, ER, and oxidative stress in the heart, which over time leads to the accumulation of oxidative damage, causing cellular impairment, highlighting these pathways as potential therapeutic targets for mitigating age-related cardiac dysfunction.

Background: Immune checkpoint inhibitors (ICIs) have changed the landscape in oncology, providing effective cancer management for a growing population. However, by promoting an immunological attack on cancer cells, healthy cells may be harmed in the process. Increased awareness of ICI-associated myocarditis (ICIMy) as one of the most fatal immune-related adverse events has led to efforts to improve the diagnosis and treatment of this condition. The purpose of this review is to summarize the current state of knowledge regarding ICIMy. Methods: We performed a literature search in Pubmed and Scopus with the relevant keywords, screened the titles and abstracts of the results, and reviewed the selected publications using pre-established criteria. Main findings: Although ICIMy’s cumulative incidence is below 0.5% in clinical trials, real-world data reveal a higher incidence of up to 4%. Underlying pathophysiologic mechanisms include T cell clonal expansion, molecular mimicry, and increased inflammatory cytokine signaling pathways leading to ICIMy. The clinical presentation can vary from asymptomatic to fulminant cardiac death and is often accompanied by musculoskeletal adverse events. Emerging diagnostic tools with prognostic value include global longitudinal strain assessment and multiple PET-CT modalities. The mainstay of treatment includes holding the immunotherapy, prompt high-dose methylprednisolone, and close cardiovascular observation. Fulminant and refractory cases benefit from additional immunomodulatory therapies. Principal conclusions: Although ICIMy is a rare adverse event, its non-specific presentation warrants a high level of suspicion. Once ICIMy is considered a likely diagnosis, immunomodulatory therapies should be initiated promptly.