Differential Regulation of Metabolism andEpigenetic Modifiersin Aging Female and Male Mice Kidney

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The aging kidney represents a complex interplay of genetic, epigenetic, and environmental factors that contribute to systemic pathophysiological changes. Understanding the direct connections between metabolism and chromatin dynamics may uncover potential mechanisms involved in the aging process of renal physiology. We hypothesized that age and sex would differentially regulate renal metabolic pathways and metabolite cofactors of epigenetic modifiers. To test this hypothesis, we utilized kidney tissues from 4-month (M; young), 12M, and 24M (aged)-old female and male C57BL/6JN mice, kindly provided by the NIA Aged Rodent Tissue Bank, and measured metabolites in the renal homogenates by HPLC-TripleTOF (LC-MS). Urine samples of healthy human subjects from young (30-45 years) and older adults (60+ years; post-menopausal females and older males) were analyzed for validation of significant metabolites identified in the mice. Our LC-MS metabolomics analysis reveals significant age-related changes in metabolic pathways in mouse kidney tissues. The major metabolic adaptations observed with aging include increased glycolysis, decreased fatty acid oxidation, mitochondrial dysfunction, oxidative stress, and impaired metabolic waste clearance in both 24M female and male mice compared to 4M sex-matched mice. Additionally, we found elevated levels of methylation and acetylation of intermediate metabolites in aged mice compared to their younger counterparts. Sex-specific changes were observed with age such as, significantly enhanced amino acid clearance and tryptophan metabolism and reduced lysophospholipase activity and ammonia clearance in aged female vs aged male mice. Renal pyruvate levels, glycolysis product, decreased with age in 24M female and male mice compared with sex-matched 4M mice (p < 0.01). L-carnitine, an essential enzyme co-factor in β-oxidation of long-chain fatty acids was markedly lower (p < 0.05) in 24M females vs 24M male mice. Anti-aging metabolite, β-hydroxybutyrate (β-HB), an endogenous inhibitor of epigenetic enzyme, histone deacetylases, was significantly decreased (p < 0.0001) in 24M male and female mice compared with 4M and 12M sex-matched mice. In contrast, anti-aging metabolite, alpha ketoglutarate (a-KG), an intermediate of tricarboxylic acid cycle and glutamine/glutamate metabolism, and an epigenetic cofactor for histone and DNA demethylases was markedly upregulated in aged mice kidney. Translationally, in human urine samples, decreased pyruvate levels were observed in postmenopausal females compared with young females (p < 0.01) and older males (p < 0.05). Urinary L-carnitine levels were significantly lower in postmenopausal females compared with young females (p < 0.05) and higher in older vs young males (p < 0.05). In contrast with mice kidney results, urinary a-KG was reduced in postmenopausal vs young females (p < 0.0001) and older vs young males (p < 0.01). Our results reveal age- and sex-related alterations in renal metabolic pathways, characterized by an increase in epigenetically modified intermediate metabolites with aging. These findings suggest a complex interplay between renal metabolomics and epigenetics and offer new insights into the mechanisms underlying sex-specific renal physiology and the pathophysiology of aging kidneys. Funding source: NIH grant R03AG075396 (awarded to PK) and COBRE in aging and regenerative medicine (P30GM145498). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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