Introduction: Decoding How Exercise Promotes Healthy Aging
Exercise is widely recognized as a powerful intervention for maintaining physiological health and delaying age-associated decline. Regular physical activity improves cardiovascular fitness, metabolic homeostasis, immune function, and tissue resilience. However, the molecular mechanisms through which exercise reshapes systemic physiology and contributes to healthy aging remain incompletely understood.
A key challenge is that exercise is not a single biological stimulus. Acute exercise (AE) induces rapid and transient responses, whereas long-term exercise (LE) produces sustained molecular and cellular adaptations. How these distinct exercise patterns influence systemic immunity, metabolism, and aging-related pathways—and which circulating molecules mediate their beneficial effects—has remained difficult to resolve.
To address this complexity, comprehensive multi-omics profiling can provide a systems-level view of exercise-induced changes across molecular layers. In particular, plasma proteomics offers a direct window into circulating proteins associated with immune regulation, metabolism, inflammation, and tissue adaptation.
A study published in Cell systematically mapped human responses to acute and long-term exercise and identified betaine as an exercise-responsive molecule with geroprotective potential. PTM BIO contributed plasma proteomics support using Blood+DIA Proteomics, helping characterize systemic protein-level changes associated with exercise adaptation.
Research Discovery: A Multi-Omics Atlas Reveals Distinct Exercise Responses
A landmark study published in Cell, titled “Systematic profiling reveals betaine as an exercise mimetic for geroprotection,” was led by researchers from the Institute of Zoology, Chinese Academy of Sciences, in collaboration with the National Genomics Data Center and Xuanwu Hospital, Capital Medical University.
The researchers recruited 13 healthy young men and designed a longitudinal exercise paradigm comprising a 45-day baseline period with restricted physical activity, a single 5-km run representing acute exercise, and a long-term exercise program progressing from intermittent running to daily 5-km runs.
Blood and fecal samples collected before and after exercise were analyzed using an integrated multi-omics strategy, including single-cell transcriptomics, transcriptomics, plasma proteomics, plasma metabolomics, and gut microbiome and microbial metabolomics analyses.
This systematic profiling revealed distinct molecular signatures associated with acute versus long-term exercise. Acute exercise rapidly altered peripheral blood cell composition, particularly NK cells and CD8+ T cells, while plasma proteomics and metabolomics indicated activation of glycolysis, lipolysis, and fatty-acid oxidation. These changes suggested rapid metabolic and immune mobilization in response to physiological stress.
Long-term exercise generated more sustained remodeling of immune and metabolic states. Lymphocyte abundance increased while myeloid populations decreased, accompanied by changes in immune-cell migration and reduced expression of aging-associated genes. ETS1 emerged as an important molecular regulator associated with long-term exercise-induced T-cell activation, aging, and differentiation.
Importantly, multi-omics analysis identified betaine as an exercise-responsive metabolite. Subsequent mechanistic studies revealed that betaine directly interacts with TBK1, suppressing TBK1 autophosphorylation and downstream IRF3/NF-κB signaling. This provided a mechanistic link between exercise-associated metabolic adaptation and inflammatory regulation.
PTM BIO Technology Contribution: Unlocking Exercise-Responsive Biology Through Plasma Proteomics
Addressing Key Technical Challenges
Understanding systemic responses to exercise requires the ability to capture coordinated changes across circulating proteins, metabolites, immune cells, and the gut microbiome. Plasma represents a particularly information-rich but analytically challenging biological matrix, containing a highly dynamic range of protein abundances.
In this study, plasma proteomics was integrated with multiple molecular profiling approaches to characterize how exercise reshapes the circulating molecular environment. Rather than examining isolated biomarkers, the researchers sought to identify coordinated protein-level changes associated with both immediate physiological adaptation and longer-term remodeling.
Advanced Proteomics Enables Critical Discovery
PTM BIO provided plasma proteomics technical support using its Blood+DIA Proteomics workflow, contributing quantitative protein-level information to the study's multi-omics framework.
The plasma proteomic analysis revealed molecular signatures associated with distinct exercise states. Following acute exercise, changes in proteins involved in metabolic adaptation were observed alongside metabolomic alterations, including increased levels of metabolic enzymes such as hexokinase 1 (HK1) and transketolase (TKT). These findings were consistent with enhanced glycolytic activity, lipolysis, and fatty-acid oxidation, supporting the concept that acute exercise rapidly mobilizes systemic metabolic resources.
Long-term exercise produced a different molecular profile. Proteomic analysis indicated increased levels of antioxidant-related proteins such as SOD1, together with reductions in complement and other pro-inflammatory proteins. These changes complemented the transcriptomic and metabolomic findings, suggesting that sustained exercise promotes a systemic environment characterized by improved antioxidant capacity and reduced inflammatory signaling.
The integration of quantitative plasma protein profiling with other omics layers therefore enabled the research team to move beyond descriptive exercise signatures toward a more comprehensive understanding of systemic adaptation.
From Discovery Data to Biological Mechanism
The multi-omics dataset further revealed metabolic remodeling associated with long-term exercise, including activation of methionine metabolism and increased levels of methyl donors such as betaine.
Follow-up experiments in mouse exercise models demonstrated that long-term exercise significantly increased renal betaine levels. The researchers further linked betaine production to mitochondrial oxidation of choline, with choline dehydrogenase (CHDH) induced in the kidneys of exercising mice, suggesting a potential regulatory node for endogenous betaine synthesis.
Mechanistic experiments showed that betaine directly binds to TBK1, an innate immune kinase, and inhibits its activation. This suppressed downstream IRF3 and NF-κB signaling, reducing inflammatory cytokine production, including TNF-α and IL-6, as well as reactive oxygen species generation.
In aged mice, betaine supplementation improved kidney function, metabolic performance, muscle endurance, and cognitive function while reducing features associated with tissue aging, including senescent cells and lipid accumulation.
Together, these findings connect exercise-associated metabolic remodeling with immune and inflammatory regulation through a betaine–TBK1 axis, providing a mechanistic explanation for how an exercise-responsive metabolite may contribute to geroprotection.
Scientific Impact: Linking Exercise Adaptation to Geroprotection
This study provides a systematic molecular and cellular framework for understanding how acute and long-term exercise affect human physiology.
By integrating plasma proteomics, metabolomics, single-cell transcriptomics, and microbiome profiling, the researchers captured exercise responses across multiple biological layers. The findings demonstrated that acute and long-term exercise are not simply different in intensity or duration, but generate distinct molecular adaptation programs involving immune-cell dynamics, metabolic pathways, antioxidant responses, inflammation, and microbial homeostasis.
The identification of betaine as an exercise-responsive geroprotective factor further extends the biological significance of the study. Its ability to inhibit TBK1 and suppress inflammatory signaling establishes a potential molecular connection between metabolism and innate immunity.
These findings provide a foundation for investigating exercise mimetics and aging interventions and highlight the value of integrated proteomic and multi-omics strategies for discovering circulating regulators of healthy aging.
PTM BIO: Empowering Next-Generation Proteomics Research
PTM BIO provides advanced mass spectrometry-based proteomics solutions designed to support biological discovery from molecular profiling through mechanistic investigation and biomarker validation.
Our technology portfolio covers plasma proteomics, deep-coverage proteomics, quantitative proteomics, post-translational modification proteomics, and targeted proteomics, supported by high-resolution mass spectrometry and integrated bioinformatics.
For complex biological matrices such as blood and plasma, PTM BIO's proteomics workflows are designed to improve protein coverage and quantitative reproducibility, enabling researchers to investigate systemic molecular changes associated with disease, aging, metabolism, immunity, and other biological processes.
By integrating discovery proteomics, PTM proteomics, bioinformatics, and targeted validation, PTM BIO works as a scientific partner throughout the research process—from identifying molecular candidates to investigating biological mechanisms and supporting translational research.
In this Cell study, Blood+DIA Proteomics contributed plasma protein-level evidence to a comprehensive multi-omics investigation of exercise adaptation and healthy aging.
