About two thousand years ago, Hippocrates observed that “walking is man’s best medicine” [
1], a notion increasingly validated in modern society. The benefits of physical activity in preventing chronic diseases and in improving longevity have been extensively studied [
2]. Today, exercise is prescribed as therapy for numerous chronic diseases, including metabolic diseases (e.g., obesity, hyperlipidemia, type 2 diabetes), cardiovascular diseases (e.g., hypertension, coronary heart disease, heart failure), pulmonary diseases (e.g., chronic obstructive pulmonary disease, asthma, cystic fibrosis), musculoskeletal disorders (e.g., osteoarthritis, osteoporosis, back pain), psychiatric diseases (e.g., depression, anxiety, stress, schizophrenia), neurological diseases (e.g., dementia, Parkinson’s disease) and cancer [
3]. However, the molecular mechanisms underlying the benefits of exercise remain incompletely understood, hindering the development of an “exercise in a pill.” A recent study published in
Cell by Geng
et al. sheds new light on the molecular basis of aerobic exercise [
4].
The study established a well-controlled exercise protocol to compare resting conditions with either a single bout of acute aerobic exercise or 25 days of long-term aerobic exercise training in young healthy males. Through multi-dimensional characterization including physiologic parameters, physical examination, blood chemistry analyses, Olink inflammatory factors profiling, plasma proteome/metabolome assessments, single-cell transcriptome of peripheral blood cells, and fecal metabolome/microbiome assessments, the study revealed several key discoveries regarding the molecular underpinnings of both acute exercise responses and long-term exercise training adaptions.
First, acute exercise induced pronounced elevation of immune cell activation and metabolic fuel mobilization, accompanied by dramatic changes in plasma protein and metabolite levels. While long-term exercise remodeled peripheral immune cell composition and exhibited anti-inflammatory effects. Transcriptome analysis revealed substantial transcriptional-level changes in peripheral blood cell, particularly neutrophils, indicating immune system transcriptional adaption. Moreover, long-term exercise showed minimal alterations in non-esterified fatty acids (NEFAs)—a major fuel substrate during aerobic exercise [
5], which contrasts sharply with acute exercise responses and suggests metabolic adaption during exercise training. Interestingly, despite using identical moderate-intensity protocol, acute exercise following 45-day rest activated anaerobic glycolysis, whereas long-term training exhibited characteristic aerobic exercise patterns including enhanced aerobic glycolysis, fatty acids utilization, and oxidative phosphorylation, indicating improved cardiovascular functions. Consistent with this, long-term exercise reduced resting heart rate.
Second, plasma proteins upregulated by long-term exercise are primarily associated with geroprotection-related pathway, such as antioxidant defense and longevity mechanisms, while downregulated proteins are predominantly linked to cholesterol metabolism, complementary pathways, and pro-inflammatory signaling. These findings provide molecular insights into exercise-induced improvements in metabolic and immune functions. Notably, compared with acute exercise, a higher proportion of metabolites and plasma proteins functioned as hub nodes connecting multidimensional changes in long-term training. A major regulatory hub involves cholesterol metabolism-related proteins. As the fundamental building block for cellular membranes and precursor for steroid hormones/bile acids, cholesterol metabolism dysregulation underlies various chronic diseases [
6]. The observed metabolic remodeling offers a mechanistic explanation for long-term exercise adaptations. However, the specific mechanisms and magnitude of cholesterol metabolism’s contribution to exercise benefits require further investigation. Over recent decades, cholesterol-lowering therapeutics (e.g., statins, PCSK9 inhibitors, ezetimibe) have demonstrated great clinical success [
7]. Whether these pharmacological agents exhibit geroprotective effects warrants dedicated investigation.
Third, metabolomic analysis revealed significantly increased amino acid metabolism in long-term exercise compared to acute exercise, with particularly pronounced activation of renal betaine metabolism. Strikingly, betaine supplementation demonstrated antagonistic effects against inflammation and cellular senescence while conferring systemic geroprotection across multiple organ systems. Furthermore, Geng et al. discovered that betaine functions as an endogenous inhibitor of TANK binding kinase 1 (TBK1), exerting anti-inflammatory and geroprotective effects through TBK1 inhibition. These findings provide profound molecular insights into exercise benefits and suggest potential strategies for developing “exercise-mimetic” therapeutics.
In summary, Geng et al. elucidated the molecular framework of human exercise physiology, particularly at the intersection of metabolism, inflammation, senescence, and aging. This groundbreaking paradigm establishes a systematic blueprint for analyzing exercise-mimetic interventions targeting healthspan extension.
PDF
(176KB)
