Calmodulin-like skin protein (CLSP) is a secreted peptide that is restrictedly produced in skin keratinocytes and some related epithelial cells. It has been previously shown that CLSP is recruited via blood stream into the central nervous system where it likely exerts neuroprotective effect against toxicity related to Alzheimer's disease (AD) by binding to the heterotrimeric humanin receptor and activates intracellular survival signaling. However, it remains to be elucidated whether secreted CLSP has some biological activities outside the central nervous system. In the current study, using hydrogen peroxide (H₂O₂) - and ultraviolet (UV) -induced senescence models of primarily cultured skin keratinocytes, we have addressed to the question as to whether CLSP is involved in senescence of skin keratinocytes. We first found that CLSP expression was potentiated by the treatment with H₂O₂ and the exposure to UV in keratinocytes. Furthermore, the co-incubation with recombinant CLSP reduces Senescence-associated beta-galactosidase-positivity in keratinocytes that is induced by the treatment with H₂O₂ and the exposure to UV. These results suggest that CLSP may function as a senescence-suppressing factor for keratinocytes.