BEIJING— In a Cell study, researchers from the Chinese Academy of Sciences and Xuanwu Hospital discovered that exercise's anti-aging effects are mediated by betaine, a kidney-produced metabolite. This naturally occurring compound effectively mimics exercise by targeting a key inflammation regulator, opening avenues for "exercise-in-a-pill" interventions.

Over the course of a 6 - year - long research endeavor, scientists meticulously mapped the intricate human molecular responses to both single intense workouts and sustained exercise in a cohort of 13 healthy males. By employing multi - omics analysis on blood and stool samples collected during tightly controlled rest - to - exercise transitions, they uncovered a fascinating phenomenon: the kidneys play a pivotal role in orchestrating systemic geroprotective effects. Notably, betaine production experienced a significant surge specifically during long - term training, and this increase was closely correlated with reduced inflammation as well as diminished markers of cellular aging.

The study unveiled striking contrasts between the two types of exercise. Acute exercise seemed to trigger a state of metabolic chaos, characterized by spikes in cortisol levels, depletion of amino acids, and the induction of oxidative stress. In stark contrast, sustained exercise effectively reprogrammed metabolism and immunity. It led to the expansion of "youthful" na？ve T - cells while simultaneously suppressing senescence drivers such as ETS1. Crucially, the kidneys stepped up their game by boosting betaine synthesis through the enzyme CHDH.

Betaine emerged as a key molecular proxy of exercise. When administered at exercise - mimicking doses, it demonstrated remarkable effects. It was able to reverse aging in human kidney, vascular, and immune cells. In aged mice, it brought about functional improvements in metabolism, cognition, and motor skills. Moreover, it directly bound to and inhibited the TBK1 kinase, effectively blocking inflammatory cascades involving NF-κB and IRF3.

"This resolves the exercise paradox," remarked co - corresponding author Dr. Guang - Hui Liu. "Acute exercise initially triggers a survival - oriented inflammatory and oxidative stress response via the IL-6/cortisol pathway. However, long-term exercise suppresses inflammation and oxidative damage through kidney-generated betaine. "These findings position betaine as a safe, low-dose therapeutic candidate, especially for seniors with limited mobility.

This work establishes a new paradigm in the field. It shows how physiological complexity can be converted into targetable pathways. As a natural TBK1 inhibitor with dual anti-inflammatory and geroprotective effects, betaine serves as a prime example of how an "exercise-in-a-pill" approach could potentially revolutionize aging intervention.

The corresponding authors of this study are Guang-Hui Liu and Jing Qu from the Institute of Zoology, Chinese Academy of Sciences; Weiqi Zhang from China National Center for Bioinformation and Beijing Institute of Genomics, Chinese Academy of Sciences; Moshi Song from the Institute of Zoology, Chinese Academy of Sciences; and Si Wang from Xuanwu Hospital Capital Medical University.

Figure: Oral betaine effectively alleviates renal fibrosis in aged mice. Control group (left); Intervention group (right). (Image by LIU Guanghui's lab)