Histones are structures in the cell nucleus that act as spools. Regions of nuclear DNA are compacted into a protected, inactive form when spooled around histones. The modification of histones by the addition and removal of chemical decorations are an important part of determining the winding and unwinding of DNA, and thus which gene sequences are exposed to translational machinery and can be expressed at any given time. One sizable component of aging is that this highly complex regulation of DNA structure changes, altering gene expression in undesirable ways.
Researchers here take initial steps towards mapping the effects on aging of succinylation of histones, the addition of a succinyl group. Their initial data suggests that more succinylation is a good thing, in that it correlates with greater longevity and a slower pace of aging. Providing mice with a diet supplemented with succinic acid to provoke greater histone succinylation produces modest benefits. That more succinylation is beneficial in this way is an unexpectedly direct outcome for something as complex as regulation of histone function, but the data is the data.
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.
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