Resistance Training as Systemic Medicine: A Multi-Organ, Hormetic Framework for Combating Metabolic Syndrome and Extending Healthspan

Resistance Training as Systemic Medicine: A Multi-Organ, Hormetic Framework for Combating Metabolic Syndrome and Extending Healthspan

Authors: Geoffrey Onchiri Mosota¹

Affiliations:
¹ Native Inspire Africa, in association with Boyani Medical Clinic, Nairobi, Kenya.

Correspondence: Geoffrey Onchiri Mosota, Native Inspire Africa, in association with Boyani Medical Clinic, Nairobi, Kenya. Email: [email protected]

Keywords: Resistance Training, Hormesis, Exerkine, Myokine, Histone Lactylation, Insulin Resistance, Metabolic Syndrome, Sarcopenia, Healthspan, Systemic Adaptations

Abstract

Resistance training (RT) has evolved from a modality for athletic performance to a cornerstone of preventive medicine. This review synthesizes contemporary evidence to establish RT as a potent, pleiotropic intervention that orchestrates systemic adaptation beyond skeletal muscle hypertrophy. We propose a unified “Metabolic Hormesis” framework wherein RT acts as a controlled biological stressor, activating conserved adaptive networks. Key mechanisms include the induction of a multi-organ exerkine dialogue, epigenetic reprogramming via novel pathways like histone lactylation, and direct amelioration of sarcopenia. Clinically, RT robustly improves insulin sensitivity, glycemic control, and body composition, with combined training (aerobic and resistance) offering superior benefits for metabolic syndrome. We argue for the formal integration of structured RT into public health guidelines as a non-pharmacological, foundational strategy to counteract the root causes of metabolic disease and frailty, thereby compressing morbidity and extending functional healthspan in an aging global population.

Introduction

The global prevalence of metabolic syndrome—a cluster of conditions including insulin resistance, dyslipidemia, hypertension, and central adiposity—and its sequelae (type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease) represents a paramount public health challenge. Concurrently, the age-related loss of skeletal muscle mass and function, known as sarcopenia, synergistically exacerbates metabolic dysfunction and frailty, creating a vicious cycle of declining healthspan. While pharmacological management advances, there is an urgent need for foundational, non-pharmacological interventions that address core pathophysiology.

For decades, the scientific and public health emphasis has favored aerobic exercise, inadvertently marginalizing the profound systemic benefits of resistance training (RT). Traditionally viewed through the narrow lens of muscle hypertrophy and strength, RT is now recognized by integrative physiology as a potent endocrine and epigenetic stimulus. We posit that RT is a form of hormesis—a beneficial adaptive response to a moderate, intermittent stressor—that recalibrates inter-organ communication, restores metabolic flexibility, and mitigates cellular aging processes. This manuscript aims to: 1) delineate the multi-organ molecular milestones of RT, focusing on exerkine signaling and the emergent role of lactate as an epigenetic modulator; 2) synthesize high-grade clinical evidence for RT in preventing and managing metabolic disease and sarcopenia; and 3) propose a practical, evidence-based framework for implementing RT as essential medicine for longevity.

Table 1: Key Conceptual Definitions

Method Details

Literature Review Methodology

This narrative review employed a systematic approach to identify, select, and critically appraise relevant scientific literature. The primary objective was to synthesize the most current and authoritative evidence on the systemic effects of resistance training on metabolic health, longevity, and aging.

1. Search Strategy:Electronic searches were conducted in major biomedical databases, including PubMed/MEDLINE, Scopus, and Web of Science. The search strategy utilized a combination of Medical Subject Headings (MeSH) terms and keywords, including: “resistance training,” “strength training,” “weight lifting,” “myokine,” “exerkine,” “insulin resistance,” “metabolic syndrome,” “sarcopenia,” “histone lactylation,” “hormesis,” and “healthspan.” Boolean operators (AND, OR) were used to refine searches. The search was limited to articles published in English, with a focus on human studies, meta-analyses, and randomized controlled trials (RCTs) published within the last 10 years, with seminal older papers included for foundational context.
2. Study Selection:Titles and abstracts of retrieved articles were screened for relevance based on predefined inclusion criteria: studies investigating the physiological, molecular, or clinical effects of structured resistance training; research on exerkine biology and inter-organ communication; and clinical trials on RT for metabolic disease or age-related conditions. Reviews, commentaries, and animal or in vitro studies were included only if they provided critical mechanistic insights not available from human trials. Papers focusing solely on aerobic exercise without a resistance component, or on athletic performance without a health outcome, were excluded.
3. Data Extraction and Synthesis:Key data from selected articles, including study design, population characteristics, intervention details (RT protocol), outcome measures, and main findings, were extracted and organized thematically. The synthesis was structured to first establish the molecular and physiological mechanisms, then present the clinical evidence, and finally integrate these into a coherent conceptual and practical framework. Emphasis was placed on consistency of findings across multiple studies and the quality of evidence, with priority given to systematic reviews and meta-analyses.

Molecular Physiology: The Systemic Milestones of Resistance Training

The therapeutic power of RT is rooted in its capacity to induce adaptations across multiple organ systems, initiated by skeletal muscle but orchestrated through systemic communication.

1. The Endocrine Muscle: Myokines and the Exerkine Network
   Contracting skeletal muscle functions as a potent secretory organ. The release of myokines, such as interleukin-6 (IL-6), irisin (from FNDC5), brain-derived neurotrophic factor (BDNF), and myonectin, constitutes a critical milestone in understanding RT’s systemic reach. For instance, exercise-induced IL-6, contrary to its pathogenic role in chronic inflammation, acts hormonally to stimulate adipose tissue lipolysis, hepatic glucose production, and improved insulin sensitivity. Irisin is implicated in the “browning” of white adipose tissue, increasing energy expenditure. This exerkine network facilitates a real-time, multi-organ dialogue that aligns the metabolic state of the liver, adipose tissue, and brain with the physiological demand imposed by RT.
2. The Epigenetic Regulator: Lactate and Histone Lactylation
   A paradigm-shifting discovery redefines lactate from a mere metabolic waste product to a crucial signaling molecule and epigenetic precursor. High-intensity RT generates significant intramuscular lactate. Recent work reveals that lactate can be converted to lactyl-CoA, which drives histone lactylation—the addition of a lactyl group to histone proteins (e.g., at H3K18). This novel modification alters chromatin architecture and gene expression. Crucially, histone lactylation levels decline with cellular senescence and muscle aging, impairing the expression of genes involved in DNA repair and proteostasis. RT, by restoring glycolytic flux and lactate production, can rejuvenate this epigenetic landscape, promoting the expression of cytoprotective genes and representing a direct molecular link between exercise and slowed cellular aging.
3. Direct Counteraction of Sarcopenia and Inflammation
   RT is the most effective intervention for sarcopenia, targeting its multifactorial etiology. It reverses anabolic resistance by sensitizing muscle to amino acids and elevating anabolic hormones like IGF-1, while suppressing the myokine myostatin, a potent inhibitor of growth. Furthermore, RT stimulates satellite cell proliferation and fusion, essential for muscle repair and hypertrophy. Concomitantly, RT exerts a potent anti-inflammatory effect. It reduces systemic levels of pro-inflammatory cytokines (e.g., TNF-α, CRP) and stimulates the release of anti-inflammatory myokines, thereby quenching the state of chronic, low-grade “inflammaging” that underlies both insulin resistance and muscle wasting.

Clinical Translation: Evidence for Prevention, Management, and Prescription

Robust meta-analyses of randomized controlled trials (RCTs) provide authoritative evidence for RT’s clinical efficacy.

1. Metabolic Disease Outcomes

• Diabetes Prevention & Management: In adults with type 2 diabetes, RT consistently improves glycemic control. A 2025 meta-analysis of 43 RCTs concluded that RT significantly reduces HbA1c, fasting glucose, and insulin resistance (HOMA-IR), while increasing lean mass. The optimal frequency appears to be three sessions per week.
• Superiority of Combined Training: For comprehensive management of metabolic syndrome, combined training (CT) integrating RT and aerobic exercise may be superior. A 2025 network meta-analysis found CT more effective than either modality alone at improving a broader panel of risk factors, including waist circumference, triglycerides, HDL cholesterol, and blood pressure.

2. Prescription for Aging and Sarcopenic Populations
   Personalized prescription is key. Evidence supports the FITT-VP principle(Frequency, Intensity, Time, Type, Volume, Progression):

• Type: Multi-joint exercises (squats, presses, rows) recruit large muscle volumes, eliciting greater systemic hormonal and metabolic responses.
• Intensity & Volume: Moderate-to-high intensity (70-85% 1RM) for 2-4 sets of 8-12 repetitions is effective. For frail initiates, lower loads (40-50% 1RM) with higher repetitions to volitional fatigue can improve strength and function.
• Frequency: 2-3 sessions per week on non-consecutive days allows for recovery and adaptation.
• Progression: Systematic overload is non-negotiable for continued adaptation, whether through increased load, volume, or decreased rest.

*Table 2: Evidence-Based Resistance Training Prescription for Key Populations*

Discussion and Future Perspectives: Positioning RT as Foundational Medicine

We have delineated a framework in which RT acts as a multi-system modulator, protecting against metabolic and frailty syndromes through hormetic exerkine signaling, epigenetic regulation, and anabolic restoration. This compels a re-evaluation of RT’s place in public health. It must be elevated from a supplementary activity to a core component of standard care for prediabetes, type 2 diabetes, sarcopenia, and healthy aging protocols.

Future research must address critical frontiers:

1. Personalized Exerkine Profiles: Defining individual variability in the exerkine response to different RT protocols to move towards precision exercise prescription.
2. Longitudinal Epigenetic Mapping: Tracking how long-term RT influences epigenetic age (e.g., DNA methylation clocks) and tissue-specific lactylation landscapes across the lifespan.
3. Nutraceutical & Pharmacological Synergy: Identifying compounds that safely potentiate the myokine or lactylation response to RT (“exercise mimetics”), especially for individuals with limited mobility.
4. Implementation Science: Developing and testing scalable, cost-effective models for delivering supervised RT programs in community and clinical settings, particularly in low-resource environments.

Conclusion

Resistance training is a powerful, non-pharmacological form of systemic medicine. By inducing beneficial inter-organ communication via exerkines, reprogramming the epigenetic environment through mechanisms like histone lactylation, and directly building and preserving metabolically crucial lean mass, RT targets the fundamental pillars of metabolic disease and aging. Integrating structured, progressive RT into lifestyle medicine and public health policy is an urgent imperative for enhancing healthspan, compressing morbidity, and safeguarding functional independence in our aging world.

Author Contributions

G.O.M.: Conceptualization, Methodology, Investigation, Review & Editing.

Declaration of Interests

The author declares no competing interests.

References

1. Pedersen, B.K. & Febbraio, M.A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol8, 457–465 (2012). Seminal review establishing the endocrine function of muscle.
2. Zhang, D., et al. Metabolic regulation of gene expression by histone lactylation. Nature574, 575–580 (2019). Groundbreaking paper identifying histone lactylation as a novel epigenetic mechanism linked to metabolism.
3. Yan, X., et al. Effects of resistance training on metabolic health and skeletal muscle in older adults with type 2 diabetes: a systematic review and meta-analysis. Diabetes Res Clin Pract212, 111654 (2025). *Recent, comprehensive meta-analysis confirming RT efficacy in T2D management.*
4. Liu, Y., et al. Effects of combined aerobic and resistance training on metabolic syndrome: a systematic review and network meta-analysis. Sci Rep15, 9876 (2025). Evidence supporting the superiority of combined training for metabolic syndrome.
5. Cruz-Jentoft, A.J. & Sayer, A.A. Sarcopenia. Lancet393, 2636-2646 (2019). Authoritative review on the definition, pathophysiology, and management of sarcopenia, highlighting RT’s central role.
6. American Diabetes Association. 5. Facilitating Positive Health Behaviors and Well-being to Improve Health Outcomes: Standards of Care in Diabetes—2025. Diabetes Care48 (Supplement 1) (2025). Current clinical guidelines endorsing RT for people with diabetes.