Caloric Restriction Intervention Alters Specific Circulating Biomarkers of the Senescence-Associated Secretome in Middle-Aged and Older Adults With Obesity and Prediabetes in an 18-Week Randomized Controlled Trial

Cellular senescence is a biological aging process that is exacerbated by obesity and leads to inflammation and age- and obesogenic-driven chronic diseases including type 2 diabetes. Caloric restriction (CR) may improve metabolic function in part by reducing cellular senescence and the pro-inflammatory senescence-associated phenotype (SASP). We conducted an ancillary investigation of an 18-week randomized controlled trial (RCT) of CR (n = 31) or Control (n = 27) in 58 middle-aged/older adults (57.6 +/- 5.8 years; 75% Women) with obesity and prediabetes. We measured mRNA expression of select senescence and apoptosis genes in blood CD3 + T cells (qRT-PCR) and a panel of 25 plasma SASP proteins (Luminex/multiplex; ELISA). Participants randomized to CR lost -10.8 +/- 0.9 kg (-11.3% +/- 5.4%) over 18 weeks compared with +0.5 +/- 0.9 kg (+0.03% +/- 3.5%) in Control group. T-cell expression of senescence biomarkers, p16(INK4a) and p21(CIP1/WAF1), and apoptosis markers, BCL2L1 and BAK1, was not different between CR and Control groups in age, race, and sex-adjusted mixed models (p > .05, all). Iterative principal axis factor analysis was used to develop composite SASP Factors, and the Factors comprising TNFRI, TNFRII, uPAR, MMP1, GDF15, OPN, Fas, and MPO were significantly altered with CR intervention (age, sex, race-adjusted mixed model time x treatment F = 4.17, p <= .05) and associated with the degree of weight loss (R-2 = 0.12, p <= .05). Our study provides evidence from an RCT that specific circulating biomarkers of senescent cell burden are changed by CR in middle-aged and older adults with obesity and prediabetes. Future studies compare tissue and circulating levels of p16(INK4a) and pro-inflammatory SASP biomarkers in other populations, and interventions.

Automated summary

Cellular senescence is an aging process exacerbated by obesity and linked to inflammation and chronic diseases. Caloric restriction may improve metabolism by reducing cellular senescence and inflammation. This randomized controlled trial showed that caloric restriction intervention altered specific circulating biomarkers of cellular senescence in middle-aged and older adults with obesity and prediabetes.