Histone post-translational modifications (PTMs) are critical regulators of chromatin structure and gene expression, with broad implications for development, metabolism, and aging. While canonical modifications such as methylation and acetylation are well characterized, the role of histone succinylation remains poorly understood. Here, we investigated histone succinylation in the context of aging and exceptional longevity. Using mass spectrometry-based proteomics, we quantified histone succinylation in B-cells from four groups: young individuals, older individuals without parental longevity (OPUS), long-lived individuals, and offspring of long-lived individuals (OPEL). We found that histone succinylation was significantly elevated in the OPEL group compared to both young and OPUS cohorts. Nuclear proteomics further revealed enrichment of succinylated proteins in OPEL samples, supporting a role for succinylation in chromatin organization.To test whether succinate availability impacts healthspan, we supplemented middle-aged mice with succinic acid. While body weight, frailty index, and cognition were unaffected, succinic acid improved motor coordination and muscle strength. Together, our findings provide preliminary evidence that enhanced histone succinylation may serve as a protective epigenetic mechanism in individuals predisposed to exceptional longevity, and that succinate supplementation can selectively improve aspects of physical performance during aging.
The Succinate Paradox: Metabolic Waste or Epigenetic Armor?
- Institution: Albert Einstein College of Medicine (USA)
- Journal: Aging Cell (2026)
- Impact Evaluation: The impact factor of this journal is ~7.2 (Clarivate), evaluated against a typical high-end range of 0–60+ for top general science. Therefore, this is a High impact journal within the specific field of gerontology and geroscience.
In a counter-intuitive twist on the “aging is loss” paradigm, researchers at the Albert Einstein College of Medicine have identified a specific histone modification that increases in the “elite agers” of the human population. While typical aging is defined by the erosion of epigenetic markers (heterochromatin loss), the offspring of centenarians (OPEL)—a group genetically predisposed to extreme healthspan—display significantly elevated levels of histone succinylationcompared to both young controls and standard elderly subjects (OPUS).
This study bridges the gap between the Krebs cycle (metabolism) and chromatin structure (gene expression). The authors posit that Succinyl-CoA, a metabolic intermediate, donates a succinyl group to histones, physically opening chromatin to allow for enhanced DNA repair or gene maintenance. To validate this, they placed 18-month-old mice on a succinic acid diet. The result? No impact on cognition or frailty, but a distinct, significant improvement in motor coordination and muscle strength—effectively decoupling physical robustness from systemic aging.
Why it matters: This suggests that “metabolic health” isn’t just about ATP production; specific metabolites like succinate act as signaling molecules that physically remodel the genome to protect against frailty.