Targets of senescence in cardiac muscle: insights for regenerative treatments in the aged heart

INTRODUCTION: Despite considerable investment of time and funding, advancement in cardiac regenerative therapies has been slow. Results of large animal and human studies have failed to live up to the expectations of the positive pre-clinical animal studies. There are many reasons to explain the discrepancies, however a key factor is that patients in need of regenerative therapies are mostly aged, being 70 years and older. AREAS COVERED: The aging heart undergoes structural and functional changes due to biological mechanisms associated with aging. Of these, increased senescent cell burden, inflammaging, and metabolic dysfunction are particularly relevant to the heart. Targeting of senescent cells using senotherapeutics alleviates the detrimental features of cardiac aging, including myocardial dysfunction, hypertrophy and fibrosis, and activates endogenous cardiac regeneration. EXPERT OPINION: The future of myocardial regenerative therapies relies on us dissecting the pathways that regulate the phenotype of the aged heart. Whether these therapies are gene, cell or pharmacological, they must be tested in pre-clinical models and experimental medicine studies which reflect the patient population they are designed to treat. Senotherapeutics hold enormous promise as adjuncts to regenerative therapies by rejuvenating the tissue microenvironment and enhancing the resilience of the aging heart.