Simple molecules make difference: short peptides play a novel role in slowing senescence

Aging studies have entered a transformative era with the discovery and application of short peptides as regulators of senescence. These short peptides are encoded by small open reading frames in nuclear, mitochondrial, and viral genomes. Unlike non-coding RNAs, short peptides are evolutionarily conserved and play a role in ameliorating decline of cellular function. It has now been recognized involved in nearly all biological processes, including diseases and senescence, however, the mechanisms behind it are complicated and largely unexplored. This review aims to summarize the evidence that short peptides slow senescence by targeting interactions with core aging hallmarks in animals. The cross-species studies were reviewed from nematodes to mammals, in which short peptides can modulate the aging-related targets precisely, such as sarco/endoplasmic reticulum (SR/ER) calcium (Ca²⁺)-ATPase (SERCA) pumps and Bcl-2-associated X protein complexes. In parallel, the disorder of these short peptides accelerates age-related pathologies, while therapeutic administration extends healthspan in different animal models. Short peptides achieve disproportionate biological functions while challenges remain in peptide detection, delivery, and mechanistic decoding, yet engineered variants and gene therapies hold promise for clinical translation. By bridging molecular simplicity with systemic resilience, short peptides redefine strategies for healthy aging.