Biological and epigenetic markers of aging-related alterations in cancer survivors: a systematic review and meta-analysis

With growing populations of cancer survivors (CS), late effects of cancer treatments have emerged as a public health concern. Cancer treatments could be associated with aging-related biological alterations. However, findings remain sparse. This systematic review (SR) aims to synthesize evidence on biological and epigenetic markers of aging-related alterations in CS compared with cancer-free controls. This SR was performed in accordance with PRISMA guidelines. MEDLINE and Embase were searched for observational studies comparing biological and epigenetic biomarkers of aging-related processes between CS and cancer-free controls. Eligible biomarkers covered biological processes implicated in aging mechanisms. Two reviewers independently performed study selection, data extraction, and risk-of-bias assessment. Meta-analyses were performed using random-effects models to estimate pooled effect sizes, expressed as standardized mean differences (SMD), and heterogeneity was assessed (I²). Certainty of evidence was assessed using GRADE for exposure questions. Among 11,007 screened references, 22 studies were included. Studies were mainly cross-sectional and retrospective, with sample sizes ranging from 21 to 21,144, including mainly childhood ( n = 9) and breast cancer populations ( n = 8). The most frequently investigated aging-related biomarker domains included inflammatory processes ( n = 9), followed by epigenetic age measures ( n = 7), immune activation ( n = 2), and DNA damage ( n = 2). Meta-analyses identified significantly higher (hs)CRP levels in CS versus cancer-free controls (k = 7; 6 independent cohorts; n = 15,544; SMD = 1.06, 95% CI: 0.01–2.11; p-value = 0.049; I² = 97.7%) and higher epigenetic age-acceleration estimates in an exploratory clock-level synthesis (3 independent cohorts; 7 clock-specific estimates; SMD = 0.31, 95% CI: 0.13–0.50; p-value = 0.006; I²=84.2%). In a cohort-level sensitivity analysis restricted to the Horvath clock, the pooled estimate remained positive but not significant (3 cohorts; SMD = 0.21, 95% CI: -0.35–0.78; p-value = 0.24; I²=68.4%). Consistent patterns emerged across analyses by treatment and life-stage at cancer. GRADE certainty was moderate for CD4⁺ naïve T-cell depletion and low for all other pooled outcomes. Cancer survivors appear to exhibit aging-related biological alterations, including elevated systemic inflammation, higher epigenetic age-acceleration estimates, and immune remodeling. These findings are compatible with the accelerated-aging hypothesis but do not demonstrate a faster aging trajectory, given the heterogeneity and predominantly cross-sectional designs. Longitudinal studies are needed to determine whether these alterations reflect an increased rate of biological aging over time and translate into clinical aging outcomes.