Biology subjects

Knufinke, M.

Publications and source records attributed to Knufinke, M..

2 recordsLinked to original sources

bioRxiv2026

Effects of long-term fasting: longitudinal epigenetic responses in humans

Prolonged fasting induces marked metabolic adaptations, but whether such time-limited yet intensive interventions engage molecular processes related to biological aging in humans remains unclear. To address this, we investigated physiological and epigenetic responses to a 12-day medically supervised fasting intervention with longitudinal follow-up in 32 participants. Fasting elicited coordinated systemic physiological changes across metabolic and hematological parameters, with partial persistence at one month. Genome-wide DNA methylation analyses revealed modest but detectable CpG-level changes, primarily emerging at follow-up and distributed across genomic contexts. In parallel, epigenetic aging clocks showed clock-specific and time-dependent responses, with substantial inter-individual variability. Lower baseline epigenetic age acceleration was consistently associated with greater fasting-induced weight loss, suggesting a link between epigenetic state and metabolic responsiveness. Together, these findings indicate that prolonged fasting induces coordinated physiological adaptations alongside structured changes in epigenetic aging measures that are not captured by conventional clinical biomarkers. This study highlights epigenetic clocks as integrative molecular readouts for probing aging-related responses to short-term metabolic interventions, while also delineating their current interpretive limits.

genomics↗

bioRxiv2026

Pharmacologic AMPK Activation Extends Lifespan in C. elegans and Improves Aspects of Healthspan in Mice

Dysregulated energy metabolism is a hallmark of aging. Many interventions that extend lifespan converge on the conserved master regulator of energy metabolism, AMP-activated kinase (AMPK), and direct genetic activation of AMPK extends lifespan in multiple species. Here, we test the ability of a specific and potent pharmacologic AMPK activator, MK-8722, to extend lifespan in C. elegans and improve healthspan in aged mice. Treatment with MK-8722 from adulthood significantly extended lifespan in an AMPK-dependent manner in both wildtype and Cockayne syndrome model csb-1 mutant C. elegans, without impairing motility or reproductive capacity. Mice treated with MK-8722 from 18 until 24 months of age had significantly reduced body fat accumulation, blocked age-associated declines in fasting blood glucose and enhanced circadian rhythmicity in respiratory quotient, suggesting an improved overall metabolic state. Hepatic RNA sequencing revealed a decrease in inflammation-related pathways and an increase in sterol metabolic pathways, which was consistent with significantly increased levels of multiple sterol-derived metabolites, including lithocholic acid, a proposed mediator of the benefits of caloric restriction. Our results support pharmacologic AMPK activation as a promising gerotherapeutic strategy.

physiology↗