Effects of anti-aging diets and exercise on age-related musculoskeletal diseases via gut microbiota modulation

Abstract

Introduction

This review summarizes evidence on how anti-aging diets and exercise influence age-related musculoskeletal diseases through modulation of the gut microbiota. With population aging, these diseases are public health concerns. The gut microbiota regulates bone, joint, and muscle health via the gut‑joint, gut‑bone, and gut‑muscle axis. Few reviews integrate diet-exercise synergy with mechanistic pathways linking microbial changes to tissue outcomes.

Discussion

Anti‑aging dietary strategies, classified into caloric restriction (ketogenic diet, fasting‑mimicking diet, intermittent fasting, time‑restricted feeding) and isocaloric nutrient restriction (e.g. protein or amino acid restriction), reshape gut microbiota composition and function. Caloric restriction and intermittent fasting reduce inflammation and benefit joint and muscle health, whereas long‑term ketogenic or protein/amino acid restriction may adversely affect bone density and muscle anabolism. Moderate exercise increases microbial diversity, enriches beneficial taxa (Akkermansia, Bifidobacterium), and boosts short‑chain fatty acid (SCFA) production, especially butyrate. Exercise also strengthens intestinal barrier integrity, reduces lipopolysaccharide (LPS)‑induced systemic inflammation, and alleviates osteoarthritis (OA), bone loss, and sarcopenia in preclinical models. Combined diet and exercise may provide greater benefits than either alone. However, most evidence derives from animal or small human studies, and causality remains unclear. Future research should clarify causal mechanisms via multi‑omics and germ‑free models.

Conclusion

This review suggests that both anti-aging diets and moderate exercise may improve age-related musculoskeletal diseases partly through gut microbiota modulation. Given substantial inter‑individual variability, future research should prioritize personalized nutrition and exercise prescriptions tailored to microbiota, genetic background, and lifestyle. These findings inform precision strategies to promote healthy aging.

1. Introduction

With the ongoing global demographic shift toward an aging population, age-related diseases, particularly musculoskeletal disorders, have emerged as significant public health concerns that warrant urgent attention [1–3]. Recent studies have identified the gut microbiota as an important modulator of human aging [4], with microbial imbalance playing a contributory role in the development of age-associated musculoskeletal disorders [1–3]. For instance, a reduction in beneficial bacteria can elevate inflammatory mediators, disrupting bone metabolic balance [5], while dysbiosis may also impair nutrient absorption, compromising skeletal health [6]. These effects are mediated through the gut-joint, gut-bone, and gut-muscle axis, making the microbiota a promising therapeutic target for combating age-related musculoskeletal diseases.

Notably, the gut microbiota is highly dynamic and responsive to environmental factors, particularly diet and exercise. This plasticity allows for the design of targeted lifestyle interventions to reshape the microbiome and promote musculoskeletal health. Among these interventions, anti-aging diets (broadly classified into caloric restriction and isocaloric nutrient restriction [7]) and structured exercise (as categorized by the American College of Sports Medicine (ACSM)[8]) are two critical strategies. Moderate-intensity physical activity reduces the risk of accelerated aging, whereas prolonged intense exercise may have the contrary effect [9], highlighting the importance of appropriate exercise prescription. Although previous studies have separately examined the effects of diet or exercise on gut microbiota, few have systematically integrated their synergistic effects on musculoskeletal aging. Moreover, most existing reviews focus on descriptive associations rather than mechanistic pathways linking microbial changes to specific tissue outcomes in bone, joint, and muscle. For instance, direct evidence that exercise-induced gut microbiota modulation improves musculoskeletal health remains limited. Recent preclinical studies have begun to fill this gap: moderate exercise reduces gut-derived lipopolysaccharide (LPS) and attenuates osteoarthritis (OA) progression in mice [10], and prevents high-fat diet-induced bone loss via microbial remodeling [11]. These findings support the concept that exercise is not only a biomechanical but also a microbiota-mediated strategy.

Based on the available mechanistic and translational evidence, this narrative review aimed to examine whether anti-aging dietary strategies and exercise may influence osteoarthritis, osteoporosis, and sarcopenia through gut microbiota-related pathways, and to assess the plausibility and limitations of a combined diet–exercise–microbiota synergy model.

2. Gut microbiota

2.1. Gut microbiota in aging

The human gut microbiota is the microbial ecosystem present in the gastrointestinal tract and includes a wide range of microorganisms including bacteria, archaea, eukaryotes and viruses [12]. Through long-term symbiosis with the host, these microorganisms play indispensable roles in maintaining physiological homeostasis by participating in nutrient metabolism, synthesis of bioactive compounds, and immune regulation. In particular, microbial enzymatic activities facilitate the production of vitamins, amino acids, and SCFAs, which collectively contribute to food digestion, xenobiotic metabolism, and host metabolic balance [13].

Disruption of this balanced microbial ecosystem, commonly referred to as gut dysbiosis, is characterized by reduced microbial diversity and loss of beneficial taxa. Such alterations compromise gut barrier integrity, leading to increased intestinal permeability and impaired metabolic and immunological functions. The subsequent translocation of microbial components into systemic circulation promotes immune dysregulation and chronic low-grade inflammation, with broad consequences for systemic health [14]. During aging, gut dysbiosis becomes more pronounced and is increasingly recognized as a key contributor to age-related chronic diseases. Age-associated impairment of intestinal barrier function facilitates microbial translocation, exacerbating inflammatory signaling and immune dysfunction. This process has been implicated not only in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, but also in musculoskeletal degeneration [15]. Persistent inflammation accelerates bone loss and muscle atrophy, hallmark features of musculoskeletal conditions including osteoporosis (OP) and sarcopenia [15–17]. Additionally, dysbiosis-induced reductions in SCFAs availability may further disrupt energy metabolism and osteoimmune homeostasis, thereby increasing fracture risk [13,16].

Advancing age is accompanied by substantial alterations in gut microbiota composition, function, and metabolic capacity. These changes include a decline in beneficial microbes such as Akkermansia and bifidobacteria, alongside an expansion of taxa associated with inflammatory states, including members of Bacteroidaceae and Lachnospiraceae [16]. Functionally, the aging microbiome exhibits reduced potential for SCFA biosynthesis and carbohydrate fermentation [17], coupled with enhanced protein degradation pathways. Collectively, these shifts contribute to metabolic dysregulation, impaired immune modulation, and compromised epithelial barrier integrity [16]. Changes in the gut microbiota during human health and aging are summarized in Table 1.

Table 1.

The change of gut microbiota in human health and aging.

Change	Age-related changes	Association with age-related diseases	References
Composition and function	Beneficial bacteria (e.g. Akkermansia) decrease; certain bacteria (e.g. Faecalibacterium, Bacteroidaceae, Lachnospiraceae) increase.	Linked to inflammatory bowel disease, obesity, etc.	[4,18]
Metabolic function	Carbohydrate metabolism decreases; SCFA synthesis (especially butyrate production) decreases.	Contributes to chronic inflammation and degenerative diseases.	[19]
Microbial diversity	Diversity decreases; beneficial bacteria (e.g. bifidobacteria) decline.	Associated with chronic inflammation, immune dysfunction, and metabolic disorders.	[12,18]
Gut barrier function	Intestinal permeability increases; barrier function weakens.	Exacerbates inflammatory bowel disease, obesity, etc.	[15]
Immune regulation	Immune regulation weakens; chronic inflammation increases.	Linked to rheumatoid arthritis, cancer, etc.	[15,19]

Through the convergence of chronic inflammation, barrier dysfunction, and metabolic imbalance, the aging gut microbiota emerges as a central driver of degenerative processes. Maintaining microbial homeostasis may therefore represent a critical strategy for promoting healthy aging and mitigating the development of age-related musculoskeletal disorders. The following sections will focus on the gut–joint, gut–bone, and gut–muscle axis to elucidate the specific mechanisms by which gut dysbiosis contributes to musculoskeletal pathology.

2.2. The gut–joint axis in age-related musculoskeletal diseases

Building upon the foundational changes of the aging gut microbiota, we first examine its impact on joint health. The concept of the ‘gut-joint axis’ has gained considerable traction, illustrating how systemic effects originating from the gut can profoundly influence peripheral joint tissues. Alterations in the gut microbiota can influence joint health through multiple pathways and contribute to the pathogenesis of various forms of arthritis. Research has increasingly highlighted the association between gut microbiota dysbiosis and the pathogenesis of musculoskeletal diseases, such as OP, OA, and sarcopenia [20–23]. These conditions share common features of chronic inflammation, altered immune regulation, and impaired tissue homeostasis, all of which may be influenced by microbial imbalance.

Growing evidence has clarified the close link between gut microbiota dysbiosis and the development of arthritis, particularly OA. Current understanding indicates that the intestinal microbiota exerts a substantial influence on joint health through coordinated effects on intestinal barrier integrity, immune regulation, and neuroimmune signaling. The immune and non-immune pathways involved in this gut–joint interaction are summarized in Table 2. The intestinal barrier, formed by epithelial cells and intercellular tight junctions, plays a central role in preventing the systemic dissemination of luminal toxins and microbial products [22]. Disruption of microbial homeostasis compromises this barrier, resulting in increased intestinal permeability and enhanced translocation of pro-inflammatory mediators such as LPS into the circulation. This process intensifies joint inflammation and accelerates osteoarthritic progression [21,23]. Clinical and experimental findings consistently show that higher circulating LPS levels correlate with greater knee OA severity, underscoring the contribution of gut-derived inflammatory signals to joint degeneration [21]. In addition, microbial imbalance activates inflammasome pathways within the intestinal mucosa, initiating localized inflammatory responses that further destabilize epithelial integrity and tight junction architecture. This effect is partly mediated by increased zonulin expression, which facilitates the passage of microbial antigens into systemic circulation [24,25]. Subsequent immune activation is characterized by elevated pro-inflammatory cytokine production and enhanced differentiation of T helper 17 cells (Th17 cells). These immune populations can migrate to joint tissues, where they amplify synovial inflammation and promote cartilage degradation, a defining feature of inflammatory OA [26]. In contrast, beneficial microbial metabolites such as butyrate confer protective effects on joint homeostasis. Butyrate strengthens intestinal barrier integrity by enhancing the expression of tight junction components, including occludin and claudins, while simultaneously attenuating systemic inflammatory responses. Through inhibition of histone deacetylase (HDAC) activity, butyrate promotes the differentiation and functional stability of regulatory T cell (Treg), thereby limiting pro-inflammatory immune signaling and alleviating arthritic pathology [27]. Experimental evidence further indicates that supplementation with butyrate-producing probiotics mitigates cartilage degradation and reduces pain severity in OA models. Collectively, these findings highlight the dual role of the gut microbiota in joint health. Microbial dysbiosis can aggravate OA by increasing intestinal permeability and sustaining systemic inflammation, whereas a balanced microbial ecosystem offers therapeutic potential through immune regulation and reinforcement of the intestinal barrier. This bidirectional relationship forms the basis of the gut–joint axis, a regulatory network in which microbial homeostasis critically shapes joint integrity and disease progression. Beyond joint pathology, analogous microbiota-mediated signaling pathways extend to skeletal metabolism, giving rise to the equally important gut–bone axis, which will be discussed in the following section.

Table 2.

Gut–joint axis: immune and non-immune mechanisms regulating joint metabolism.

Gut-derived molecules	Immune-mediated mechanisms	Non-immune mechanisms	Effects on joint metabolism
SCFAs (butyrate, acetate, propionate)	• Treg differentiation↑ • Suppression of Th17 cells and IL-17A production • Reduced macrophage M1 polarization and TNF-α release	• Reinforcement of intestinal barrier integrity via tight junction upregulation • Reduced systemic endotoxemia • Direct modulation of chondrocyte metabolism via GPR41/43 signaling	• Attenuation of synovial inflammation •Reduced cartilage matrix degradation • Preservation of joint metabolic homeostasis
Bile acids (primary & secondary)	• Activation of FXR and TGR5 → inhibition of NF-κB–dependent inflammatory signaling • Downregulation of TNF-α and IL-1β	• Regulation of lipid and glucose metabolism in joint tissues • Modulation of chondrocyte autophagy and cellular senescence	• Maintenance of cartilage homeostasis • Protection against inflammation-driven joint degeneration
LPS	• TLR4–MyD88–NF-κB activation → TNF-α, IL-6, IL-17A release • Promotion of Th17 differentiation and migration to joints	• Disruption of intestinal tight junctions → increased gut permeability • Direct induction of catabolic enzymes (MMPs, ADAMTS) in chondrocytes and synoviocytes	• Exacerbation of synovitis • Accelerated cartilage catabolism • OA progression and pain aggravation

2.3. The gut–bone axis in age-related musculoskeletal diseases and its positive impacts on bone health

Emerging evidence indicates that gut microbiota dysbiosis contributes to bone loss and OP through metabolic, immune-mediated, and endocrine pathways. The gut microbiota regulates calcium and nutrient absorption, modulates systemic inflammation, and influences osteoclast–osteoblast balance, thereby shaping bone remodeling dynamics. Consistent with these mechanisms, several experimental and clinical studies substantiate the gut–bone axis. In a high-fat diet mouse model, dysbiosis induced significant bone loss [28], whereas depletion of the intestinal microbiota through antibiotic treatment increased bone mass, improved bone microstructure, and enhanced bone strength [29]. Clinical data further demonstrate associations between gut microbial imbalance and primary OP, postmenopausal OP, and fracture risk [30,31], collectively underscoring the critical influence of gut microbiota composition on skeletal integrity. The immune and non-immune mechanisms underlying the gut–bone axis are summarized in Table 3.

Table 3.

Gut–bone axis: immune and non-immune mechanisms regulating bone metabolism.

Gut-derived molecule	Immune-mediated mechanisms	Non-immune mechanisms	Net effect on bone metabolism
SCFAs (butyrate-dominant)	• ↑ Tregs / ↓ Th17; • ↓ TNF-α & IL-17; • ↑ CD8⁺ T cell–derived Wnt10b → activation of Wnt/β-catenin signaling	• GPR41/43 activation; • HDAC & NLRP3 inhibition; • ↑ OPG / ↓ RANKL; • enhanced intestinal barrier integrity	Anabolic: ↑ osteoblast differentiation, ↑ bone formation, ↑ BMD
Bile acids	• FXR/TGR5 signaling → ↓ TNF-α, IL-6; • promotion of anti-inflammatory macrophage (M2) phenotype	• Regulation of energy metabolism; • direct suppression of osteoclast differentiation via FXR/TGR5	Protective: preservation of bone mass, ↓ bone resorption
LPS	• TLR4–NF-κB activation → ↑ IL-1β, TNF-α, IL-6, RANKL; • enhanced osteoclastogenesis	• Increased intestinal permeability; • systemic endotoxemia and chronic inflammation	Catabolic: ↑ bone resorption, bone loss, ↑ fracture risk

Firstly, the gut microbiota affects bone health through metabolic products such as SCFAs [31]. Produced by bacterial fermentation of indigestible carbohydrates [32], SCFAs reach bone tissue via diffusion, transporter-mediated uptake, or by bindingto G protein-coupled receptor 41 (GPR41) and G protein-coupled receptor 43 (GPR43)[33]. At physiological levels, especially butyrate, SCFAs promote osteoblast differentiation, enhance osteoprotegerin (OPG) expression, and suppress receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis, partly through inhibition of the NLR family pyrin domain containing 3 (NLRP3) inflammasome and HDAC activity [34,35]. SCFAs also induce regulatory T cells (Tregs), which inhibit bone resorption and stimulate CD8⁺ T cell–derived Wnt10b to activate osteogenic Wnt signaling [36]. In addition, SCFAs strengthen intestinal barrier integrity and reduce systemic inflammation [36,37], indirectly benefiting bone metabolism. Secondly, the gut microbiota regulates bone health through immune modulation. T cells in the bone marrow include Tregs, which suppress osteoclastogenesis, and Th17 cells, which enhance bone resorption by secreting cytokines such as interleukin-17(IL-17), RANKL, and tumor necrosis factor-alpha (TNF-α)[38–40]. Gut microbial composition influences T cell differentiation and cytokine levels; germ-free mice exhibit reduced monocytes and osteoclasts, which are restored after microbial recolonization [41]. Probiotics such as Bifidobacterium and Lactobacillus acidophilus modulate macrophage and monocyte activity and promote TGF-β-mediated Treg differentiation, thereby maintaining immune homeostasis [42].

Thirdly, the gut microbiota affects bone health by maintaining intestinal barrier integrity. Impaired intestinal barrier function increases intestinal permeability, allowing pathogens and toxins to enter the bloodstream and trigger systemic inflammation, which directly influences bone metabolism [39]. For example, transplanting gut microbiota from aged or osteoporotic rats into young rats decreased zonulin expression, indicating impaired barrier function, which led to reduced bone mass and increased bone turnover markers [40]. This confirms that gut microbiota dysbiosis can damage the intestinal barrier and induce OP.

Finally, endocrine regulation also plays a crucial role. Hormones such as parathyroid hormone (PTH) and insulin-like growth factor-1 (IGF-1) are involved in bone health. Continuous PTH exposure enhances bone resorption, while intermittent PTH administration stimulates bone formation [41–43]. IGF-1 promotes osteoblast differentiation and collagen deposition but may stimulate bone resorption if excessive. Germ-free mice exhibit lower serum IGF-1 levels, shorter femurs, and reduced bone mass [44], while colonization restores IGF-1 levels and improves bone growth [45], indicating that IGF-1 is a key mediator in gut microbiota–mediated bone formation.

In summary, the gut–bone axis operates through multiple integrated mechanisms involving gut microbiota and their metabolites, immune regulation, endocrine hormones, and intestinal barrier function. These findings provide new insights for preventing and treating bone diseases such as OP by modulating the gut microbiota and immune system. Maintaining a balanced gut microecology is crucial for promoting skeletal health. Having established the microbiota’s role in regulating bone mineral density and turnover, it becomes evident that its influence extends to the soft tissues of the musculoskeletal system. The recently defined ‘gut-muscle axis’ completes this picture, linking gut microbial status to sarcopenia and muscle function.

2.4. The gut–muscle axis in age-related musculoskeletal diseases

The gut–muscle axis describes the bidirectional interaction between intestinal microbiota and skeletal muscle, particularly relevant during aging. Growing evidence shows that gut microbiota shapes muscle mass, strength, and fiber composition. For example, Yan et al. demonstrated that fecal microbiota transplantation induces structural remodeling in germ-free mouse muscle [46], while Siddharth et al. reported that aged sarcopenic rats exhibit reduced microbial genes involved in nutrient metabolism, correlating with impaired muscle mass and function [47].

The influence of the gut microbiota on skeletal muscle health is mediated through multiple, interconnected pathways. These include maintenance of intestinal barrier integrity, regulation of systemic inflammatory tone, production of microbiota-derived metabolites, and modulation of mitochondrial function. The immune-dependent and immune-independent processes that define the gut–muscle axis are summarized in Table 4. With advancing age, microbial imbalance compromises epithelial barrier function, allowing bacterial components such as LPS to enter the systemic circulation. This translocation activates inflammatory signaling cascades and elevates circulating pro-inflammatory mediators, including TNF-α, interleukin-6 (IL-6), and C-reactive protein (CRP). Sustained inflammation, in turn, promotes muscle catabolism by suppressing anabolic pathways mediated by Akt/mTOR signaling, while simultaneously enhancing proteolytic activity, thereby contributing to age-related muscle wasting [46,48–50].

Table 4.

Gut–muscle axis: immune and non-immune mechanisms regulating muscle metabolism.

Gut-derived molecule	Immune-mediated mechanisms	Non-immune mechanisms	Net effect on muscle metabolism
SCFAs (butyrate-dominant)	• Inflammatory cytokine suppression (TNF-α, IL-6); • relief of anabolic resistance	• AMPK–PGC-1α activation; • insulin sensitivity enhancement; • mitochondrial biogenesis; • oxidative fiber-type shift	Anabolic: ↑ muscle mass and strength
Bile acids (CA, DCA)	• FXR/TGR5-mediated inflammatory modulation	• FXR/TGR5 signaling; • energy expenditure regulation; • mitochondrial stress (dysbiosis)	Context-dependent: metabolic support or muscle loss
LPS / barrier dysfunction	• TLR4–NF-κB activation; • pro-inflammatory cytokine production; • Akt/mTOR inhibition; proteolytic pathway activation	• Increased intestinal permeability; • systemic endotoxemia; • chronic low-grade inflammation	Catabolic: muscle protein breakdown, sarcopenia

Microbiota-derived metabolites, particularly SCFAs such as butyrate and acetate, play crucial roles in muscle metabolism. Butyrate enhances insulin sensitivity, glucose uptake, and mitochondrial biogenesis by activating pathways involving AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), thereby supporting oxidative metabolism and muscle fiber-type switching [46,47,51]. Conversely, reduced SCFA levels may contribute to insulin resistance and lipid accumulation in muscle, exacerbating muscle loss. Acetate has been associated with both beneficial and adverse effects on muscle health, which may depend on metabolic context, including host insulin sensitivity, baseline inflammatory status, diet composition, exercise status, and the relative balance among SCFAs. Under physiologic conditions, acetate may support energy metabolism and mitochondrial function, whereas excessive acetate production in dysbiotic or metabolically impaired states may contribute to lipid accumulation, insulin resistance, or inflammation-related muscle dysfunction [52,53].

Mitochondrial dysfunction is another key mechanism linking gut microbiota to muscle aging. Evidence suggests that specific microbes, such as Atopobium parvulum, correlate negatively with mitochondrial protein expression and butyrate production, impairing mitochondrial function and accelerating sarcopenia [54,55]. Additionally, bile acids like cholic acid (CA) and deoxycholic acid (DCA) may induce mitochondrial dysfunction through TGR5-mediated activation of proteolytic and apoptotic pathways [56].

Beyond these mechanisms, the gut microbiota also influences muscle health through endocrine pathways, including modulation of IGF-1 and sex hormones [57]. Microbial metabolites such as phenolic compounds enhance glucose uptake and anabolic responses in muscle [58], while bile acids promote energy expenditure and reduce fat deposition via farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) signaling [59,60].

Collectively, the gut microbiota shapes skeletal muscle health through an integrated network encompassing metabolite-mediated signaling, inflammatory control, mitochondrial regulation, and endocrine influences. This mechanistic framework highlights the gut–muscle axis as a promising therapeutic target, with strategies such as microbiota-focused interventions and age-adapted dietary approaches offering potential to attenuate musculoskeletal decline associated with aging (Figure 1).

Figure 1.

Aging‑associated gut dysbiosis, characterized by reduced microbial diversity, decreased short‑chain fatty acid production, and increased intestinal permeability, promotes systemic inflammation and immune dysregulation. Through the gut‑bone, gut‑joint, and gut‑muscle axes, these changes contribute to osteoporosis, osteoarthritis, and sarcopenia by impairing bone formation, enhancing synovial inflammation and cartilage degradation, and promoting muscle atrophy.

The established roles of the gut-joint, gut-bone, and gut-muscle axis inevitably lead to the question: how can we therapeutically target these pathways? Lifestyle interventions, particularly diet, represent a primary and modifiable strategy to reshape the gut microbiota and, consequently, mitigate age-related musculoskeletal decline.

2.5. Potential and challenges of targeting the gut microbiome

Despite robust evidence supporting the role of gut microbiota across the gut-joint, gut-bone, and gut-muscle axis, significant challenges remain for clinical translation. Firstly, mechanistic insights are largely derived from animal models, whose microbiomes differ substantially from humans, necessitating caution in extrapolating findings. Secondly, the high degree of inter-individual variability in gut microbiota composition, influenced by genetics, geography, and long-term diet, suggests that universal intervention strategies may be ineffective. For instance, the efficacy of specific probiotics in improving bone density can vary significantly across populations. Moreover, the directionality of the microbiota–disease relationship remains insufficiently defined. It is often unclear whether microbial dysbiosis actively drives disease progression or whether disease-associated factors such as chronic inflammation and reduced mobility subsequently reshape the gut microbial landscape. Addressing this knowledge gap will require more stringent causal validation. Future studies should integrate approaches such as fecal microbiota transplantation, targeted microbial depletion, and germ-free animal models to disentangle cause–effect relationships and strengthen translational relevance.

3. Anti-aging diets

Given that the gut-joint, gut-bone, and gut-muscle axis are critically shaped by microbial composition and function, dietary interventions that modulate the gut microbiota represent a promising strategy to prevent or delay age-related musculoskeletal decline.

3.1. Definition and classification of anti-aging dietary paradigms

Anti-aging diets encompass nutritional strategies that modulate metabolic, inflammatory, and cellular pathways linked to musculoskeletal aging. For conceptual clarity, these dietary patterns can be organized into three mechanistic categories: energy-restriction paradigms, macronutrient-adjustment paradigms, and fasting-mimicking diets [61,62]. These modalities may exert systemic effects partly through microbiome-mediated metabolic remodeling.

Energy-restriction paradigms – including caloric restriction (CR), intermittent fasting (IF), and time-restricted feeding (TRF) – reduce energy availability or feeding windows. CR typically imposes a 20–40% reduction in caloric intake, attenuating low-grade inflammation and supporting musculoskeletal integrity. IF and TRF additionally influence circadian microbial oscillations, enrich taxa such as Akkermansia, and reduce metabolic endotoxemia. Macronutrient-adjustment paradigms include ketogenic diets (KD) and protein or amino-acid restriction. KD reshapes the microbial ecosystem via shifts in bile-acid pools and enrichment of taxa associated with mucosal immune regulation. Protein or amino-acid restriction activates nutrient-sensing pathways but may compromise skeletal and muscular anabolism. Fasting-mimicking diets (FMDs) reproduce metabolic features of fasting through low-calorie, low-protein, but micronutrient-replete regimens. FMDs induce fasting-like metabolic and hormonal adaptations relevant to musculoskeletal aging.

FMDs increase Lactobacillus and Bifidobacterium, promote SCFA generation, and dampen systemic inflammation, supporting bone metabolism and muscle regenerative capacity [63,64]. This framework provides a mechanistic basis for interpreting downstream musculoskeletal effects of each dietary modality.

3.2. Influence of anti-aging diets on age-related musculoskeletal diseases

Given the profound impact of the gut microbiota on musculoskeletal health, dietary strategies designed to modulate microbial composition offer a promising therapeutic avenue. Anti-aging dietary strategies – primarily caloric restriction (CR) and isocaloric nutrient restriction – engage conserved metabolic pathways relevant to musculoskeletal aging [7]. CR and isocaloric nutrient restriction have been shown to modulate glucose metabolism, systemic inflammation, and aging-related musculoskeletal decline. This section will specifically focus on their influence on age-related musculoskeletal diseases [65].

3.2.1. The impact of caloric restriction on age-related musculoskeletal diseases

The KD is a dietary approach that mimics the metabolic state of fasting through a high-fat, low-carbohydrate pattern. Its core mechanism is to prompt the body to produce ketone bodies as the primary energy source. The KD induces nutritional ketosis and elevates circulating β-hydroxybutyrate (β-OHB), leading to broad metabolic and anti-inflammatory effects. In OA, β-OHB suppresses NLRP3 inflammasome activation and enhances mitochondrial quality control through the HCAR2–AMPK–PINK1/Parkin axis, thereby reducing synovial inflammation, chondrocyte senescence, and cartilage matrix degradation. In osteoporosis (OP), findings are mixed. Energy and nutrient deficiencies associated with long-term KD may impair bone formation and worsen metabolic–hormonal balance; however, β-OHB may promote osteoblast differentiation and exert mild inhibitory effects on osteoclast activity. In skeletal muscle, KD improves mitochondrial biogenesis, enhances oxidative metabolism, and reduces cellular stress, thereby slowing age-related muscle atrophy. Nevertheless, possible reductions in high-intensity exercise capacity and potential bone loss highlight the need for individualized assessment before clinical application in older adults.

The FMD is a well-researched periodic dietary intervention strategy that aims to simulate the metabolic effects of fasting through a low-calorie, low-protein but unsaturated fat-rich diet. In OA, FMD reduces low-grade inflammation by activating cellular stress response mechanisms such as autophagy, mitophagy and sirtuin activation, as well as systemic hormonal and metabolic responses. The pathological mechanism of OA is partly related to low-grade inflammation, so fasting may alleviate symptoms through its anti-inflammatory effects [66,67]. FMD can alleviate age-related bone diseases. In aged mice, FMD cycles preserve bone mass, as evidenced by significantly higher femoral bone mineral density compared with controls. FMD also enhances muscle regeneration by restoring Pax7 expression in satellite cells to youthful levels and reducing p62 accumulation, suggesting improved autophagy and protection against age-related muscle decline. While preclinical findings consistently support musculoskeletal benefits, the long-term safety and efficacy in humans require further validation [68].

IF is a dietary intervention strategy that regulates metabolism and hormone levels by alternating fasting and eating periods. In OA, IF significantly alleviates inflammation, osteoclast formation, and excessive sensory nerve growth by inhibiting the overexpression of neuropeptide Y (NPY) in bone cells, thereby improving joint function, reducing pain, and delaying cartilage degeneration [69]. However, the impact of IF on OP remains inconclusive. Animal studies suggest that IF may slow bone deterioration by inhibiting osteoclast activity and promoting osteoblast formation, whereas prolonged fasting may reduce bone density and strength. Human studies have not detected significant effects of IF on bone density or bone metabolism markers [70]. Furthermore, IF may benefit muscle health by reducing oxidative stress, such as lowering the mRNA levels of glutathione peroxidase 1 (GSH-Px), superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2), and by promoting lipid metabolism, such as increasing perilipin 5 (PLIN5) expression and lipid droplet formation [71]. Overall, IF appears protective against OA, whereas its effects on OP and muscle health require further investigation.

3.2.2. The impact of isocaloric nutrient restriction on age-related musculoskeletal diseases

TRF confines daily food intake to a defined time window and improves metabolic homeostasis by reinforcing circadian rhythm alignment. TRF reduces joint inflammation by lowering IL-1β production, macrophage infiltration, and leptin levels, thereby alleviating OA–related synovial inflammation [72]. It also improves muscle metabolism by restoring mitochondrial function and reducing insulin-resistance signaling in experimental models [73]. Circadian rhythm is essential for bone turnover, and disruption of clock-gene pathways contributes to OP [74]. By restoring circadian alignment, TRF may support balanced bone remodeling and mitigate OP risk.

Protein restriction reduces protein intake while maintaining caloric stability and has been proposed as a potential anti-aging dietary strategy. However, protein restriction decreases circulating insulin-like growth factor 1 (IGF-1), which is essential for cartilage maintenance, osteoblast activity, and muscle protein synthesis. Therefore, reduced IGF-1 signaling may worsen OA progression, impair bone formation, and accelerate sarcopenia [75,76]. High-protein dietary patterns generally support calcium absorption and bone density, whereas protein restriction is associated with reduced cortical bone formation and diminished muscle mass, particularly in older adults [77]. Thus, despite its potential longevity-related benefits, protein restriction may have detrimental effects on musculoskeletal health in aging populations.

Dietary restrictions on amino acids, especially the reduction in the intake of certain essential amino acids such as methionine and tryptophan, have been proven to extend lifespan and delay age-related physiological decline. In terms of bone health, the intake of specific amino acids is closely related to bone density, which is a key indicator for preventing OP [78]. Therefore, a diet that restricts amino acids may have a negative impact on bone health. For instance, long-term restriction of methionine may lead to weight loss and increased insulin sensitivity, which in turn can negatively affect bone density and bone quality [79]. In terms of muscle health, amino acids are crucial for muscle growth and repair. Supplementing essential amino acids, such as leucine, can promote protein synthesis and inhibit muscle breakdown. Conversely, restricting amino acid intake can suppress protein synthesis, impede muscle repair, and exacerbate muscle atrophy [80,81]. Therefore, although restricting the intake of essential amino acids may extend lifespan, it can harm bone health and exacerbate muscle atrophy, thereby affecting overall physiological functions.

In anti-aging diets, calorie-restricted diets (such as KDs and fasting-mimicking diets) have shown significant anti-inflammatory and protective effects on OA and muscle health, but their impact on OP is controversial and may have negative effects. Although protein and amino acid restriction may extend lifespan, they can lower IGF-I levels, exacerbate OA, bone loss and muscle atrophy, and affect bone and muscle health. The effects of dietary interventions on age-related musculoskeletal diseases are summarized in Table 5.

Table 5.

Impact of dietary interventions on age-related musculoskeletal diseases.

Dietary intervention	Osteoarthritis	OP	Muscle health	References
Ketogenic Diet (KD)	Reduces inflammation and cartilage damage via βOHB; enhances mitophagy and chondrocyte repair.	Mainly negative: Bone metabolism imbalance, reduced density; βOHB may protect bone.	Delays muscle aging, improves mitochondrial function, reduces protein degradation.	[65,82–90]
Fasting-Mimicking Diet (FMD)	Reduces inflammation via autophagy and Sirtuin activation.	Improves bone density, slows bone loss.	Improves muscle regeneration, restores satellite cell function, and reduces age-related muscle decline	[67,68]
Intermittent Fasting (IF)	Reduces inflammation, osteoclast formation, and cartilage degeneration via NPY inhibition.	Unclear: May inhibit osteoclasts but reduce density with prolonged fasting.	Reduces oxidative stress, promotes lipid metabolism.	[70,71,91]
Time-Restricted Feeding (TRF)	Reduces inflammation via circadian rhythm regulation.	Improves bone metabolism via circadian rhythm.	Restores mitochondrial function and reduces insulin-resistance signaling, improving muscle metabolism	[72–74]
Protein Restriction	Not directly mentioned.	Reduces IGF-I, impairs bone formation, lowers density.	Inhibits protein synthesis, increases sarcopenia risk.	[75–77,92]
Amino Acid Restriction	Not directly mentioned.	Methionine restriction may reduce bone density.	Suppresses protein synthesis, worsens muscle atrophy.	[78–81]

3.3. Anti-aging diets modulate gut microbiota

Diet is a major determinant of inter-individual variability in gut microbiota, and anti-aging dietary patterns can profoundly reshape microbial composition and gut barrier function [93]. This section summarizes how key anti-aging diets modulate the gut microbiota.

The KD modulates gut microbiota, metabolite production, and immune responses. In 17 overweight or obese men, a 4-week KD decreased Bifidobacterium and increased Bacteroidetes [94]. In 12 children with severe epilepsy, a 3-month KD reduced health-promoting bifidobacteria and butyrate-producing Eubacterium rectale, while Escherichia coli increased [95]. KD or reduced carbohydrate intake also lowers fecal SCFAs, particularly butyrate, by decreasing Roseburia spp., Eubacterium rectale, and Bifidobacterium spp [96,97]. KD-induced ketone bodies, such as β-hydroxybutyrate, inhibit bifidobacteria, reducing gut pro-inflammatory Th17 cells, and suppress the NLRP3 inflammasome, decreasing IL-1β secretion [94,98]. These findings highlight that KD affects host metabolism and immunity via gut microbiota modulation, emphasizing the need to consider individual differences and long-term impacts.

IF can improve metabolic health, enhance immune function, and prevent chronic diseases by modulating gut microbiota composition and metabolic activity. IF reshapes the gut microbiota by increasing the abundance and diversity of beneficial taxa such as Akkermansia and Bacteroides, while reducing potentially harmful groups including Alistipes [99,100]. In animal studies, IF increased gut microbial diversity and maintained a stable Firmicutes-to-Bacteroidetes ratio, contributing to improved metabolic regulation [100]. Additionally, IF enhances the production of SCFAs, which support intestinal barrier integrity and immune function [101]. These findings suggest that IF exerts beneficial effects via gut microbiota modulation, though further high-quality studies are needed to clarify the underlying mechanisms.

TRF and FMD are both forms of intermittent fasting and exert health benefits primarily through reshaping gut microbiota and enhancing intestinal barrier function. FMD increases beneficial taxa such as Lactobacillus, particularly Lactobacillus johnsonii, and elevates glucose-lowering bacteria including Parabacteroides distasonis and Blautia, while reducing glucose-associated taxa such as Prevotellaceae UCG-001, Alistipes, and Ruminococcaceae UCG-01 [102]. TRF likewise modifies microbial composition, increasing Bacteroidetes and Prevotellaceae in healthy adults [103], and elevating Lachnospiraceae, Parasutterella, and Romboutsia in obese individuals [104]. In mice, combining TRF with a KD can further influence specific Bifidobacterium species [105]. Both dietary patterns also strengthen intestinal barrier function. FMD periodically enhances epithelial integrity, reduces aging markers, and maintains T-cell balance in the lamina propria in mouse models. Moreover, intermittent fasting promotes the abundance of butyrate-producing bacteria [106], and butyrate is known to reinforce epithelial barrier function [107].

Despite differing protocols, TRF and FMD consistently demonstrate beneficial effects by modulating gut microbiota composition and intestinal barrier function. A protein-restricted diet modulates gut microbiota composition and microbial metabolism by limiting protein intake. In weaned piglets, protein restriction increases the relative abundance of Firmicutes in colonic digesta while reducing Bacteroidetes, Lactobacillus, Proteobacteria, and Helicobacter in both digesta and mucosa [108]. These shifts are associated with alterations in intestinal barrier integrity [109]. Protein restriction also influences host energy metabolism by modifying the production of microbial metabolites such as SCFAs [110]. Moderate protein restriction appears to optimize gut microbiota profiles and improve mucosal barrier function [109]. Although current evidence highlights potential benefits, additional studies are required to clarify underlying mechanisms and long-term physiological impacts.

Restrictions on specific amino acids markedly reshape gut microbiota composition and related metabolic pathways. In mouse models, a sulfur amino acid–restricted (SAAR) diet produced a microbiota profile distinct from that induced by low-calorie feeding, characterized by increased abundances of Firmicutes, Clostridiaceae, and Turicibacteraceae, together with reduced Verrucomicrobia. These microbial shifts coincided with reductions in body weight and IGF-1, elevations in fibroblast growth factor 21(FGF-21) and food intake, and a shift toward glycine- rather than taurine-conjugated bile acids [111]. Methionine restriction (MR) similarly modulates the gut ecosystem, increasing short-chain fatty acid–producing taxa such as Lachnospiraceae, Turicibacter, Roseburia, and Intestinimonas [112]. The associated decrease in circulating branched-chain amino acids (BCAAs) may further contribute to improved glucose homeostasis [113]. Together, these findings show that amino acid-restricted dietary patterns exert targeted and microbiota-dependent effects on host metabolism. These interactions also establish a mechanistic basis for understanding how anti-aging dietary strategies influence the gut–bone and gut–muscle axis and motivate subsequent examination of another key microbiome modulator – physical exercise.

3.3.1. Positive impacts of gut microbiota on bone health

The gut microbiota modulates bone homeostasis through coordinated effects on microbial metabolite production, immune regulation, and intestinal barrier integrity. SCFAs, particularly butyrate, inhibit osteoclast differentiation while enhancing osteoblast function by promoting regulatory T cell–dependent induction of CD8⁺ T cell–derived Wnt10b and subsequent activation of Wnt signaling pathways [38,40]. In parallel, microbial signals shape the balance between Th 17 cells and regulatory T cells, thereby influencing the production of osteoclastogenic cytokines such as IL-17 and TNF-α. These immune mediators converge on the RANKL–RANK axis to regulate bone resorption, a relationship further supported by germ-free animal models demonstrating that osteoclastogenesis depends on microbial colonization [41,114]. Compromise of the intestinal barrier allows microbial products, including LPS, to access systemic circulation, sustaining low-grade inflammation that disrupts bone remodeling dynamics [36,48].

3.3.2. Positive impacts of gut microbiota on muscle health

The gut microbiota influences skeletal muscle health via microbial metabolites, immune modulation, mitochondrial regulation, and endocrine signalling. Microbially derived SCFAs, particularly butyrate, exert anabolic and anti-inflammatory effects on muscle: butyrate inhibits histone deacetylases, increases PGC-1α expression, promotes mitochondrial biogenesis and oxidative fiber transition, and thereby improves muscle mass and function in aged mice [10,61].

Beyond SCFAs, additional microbial metabolites – including phenolic compounds and secondary bile acids – contribute to the regulation of muscle energy expenditure and substrate utilization through activation of nuclear and membrane-associated receptors such as the FXR and TGR5 [67,68,69]. In contrast, dysbiosis-associated impairment of intestinal barrier integrity facilitates the systemic dissemination of microbial components, notably LPS, which sustain low-grade inflammation and accelerate muscle catabolism and atrophy [115]. The gut microbiota further modulates endocrine signaling by shaping circulating mediators, including IGF-1 and sex hormones, that are central to muscle anabolic balance. Together, these metabolite-driven, immune-inflammatory, mitochondrial, and endocrine mechanisms provide a coherent framework through which diet-induced alterations of the gut microbiome influence skeletal muscle health and identify multiple targets for therapeutic intervention.

3.4. The Double-Edged sword of dietary interventions and the need for personalization

The anti-aging dietary strategies discussed above remain subject to debate, as their physiological effects are highly context-dependent and vary across tissues. The KD illustrates this complexity: while it has been associated with anti-inflammatory and protective effects in OA and sarcopenia, evidence suggests that it may adversely affect bone mineral density. Such divergent outcomes underscore the challenges inherent in nutritional interventions, in which a single metabolic condition – such as sustained ketosis – can activate distinct signaling pathways and energy-utilization programs in cartilage, skeletal muscle, and bone. Similarly, while protein and amino acid restriction may theoretically promote longevity, they might directly impair anabolic processes in muscle and bone, potentially contradicting the nutritional needs of older adults.

This tissue-specific duality can be mechanistically explained by differential expression of ketone body receptors (e.g. HCAR2) and metabolic sensitivities across tissues. In cartilage,β-OHB activates HCAR2–AMPK–PINK1/Parkin axis, enhancing mitophagy and suppressing NLRP3 inflammasome, thus protecting against OA. In bone, however, long-term ketosis may impair osteoblast differentiation by limiting glucose availability and reducing IGF-1 signaling, while also promoting metabolic acidosis, which favors osteoclast activity. Similarly, protein restriction reduces IGF-1, which may extend lifespan in some models but directly compromises bone formation and muscle protein synthesis. These divergent outcomes highlight the need to evaluate dietary interventions not as uniformly beneficial or harmful, but as context-dependent modulators of specific tissues. These contradictions underscore a central question: does a universal ‘gold standard’ anti-aging diet exist? The answer is likely negative. The future lies in shifting from general recommendations to precision nutrition. This involves tailoring dietary strategies based on an individual’s age, sex, baseline microbiome profile, genetic background, and specific disease status. Therefore, the application of KD in older adults may require a risk-benefit assessment, prioritizing individuals with severe inflammatory OA or sarcopenia while monitoring bone health markers. Protein restriction might be used cautiously in older adults at high risk for sarcopenia, while periodic KD or FMD could be more beneficial for OA patients with significant inflammation.

4. Exercise

4.1. Exercise is an effective intervention for age-related musculoskeletal diseases

Exercise is a cornerstone non-pharmacological strategy for preventing and treating age-related musculoskeletal disorders, including OA, OP, and sarcopenia. With global aging, these conditions have become major determinants of disability and reduced quality of life in older adults [105]. Beyond its well-established biomechanical benefits, exercise exerts systemic effects on inflammation, metabolism, and musculoskeletal homeostasis, partly through modulation of cytokine signaling and molecular pathways. Moderate mechanical loading strengthens periarticular muscles, reduces joint stress, and suppresses inflammatory signaling in cartilage, whereas excessive loading may accelerate cartilage degeneration [106]. Exercise inhibits NF-κB activation and downregulates catabolic enzymes such as MMP-13, thereby protecting cartilage and bone integrity [107]. In bone tissue, aerobic and resistance training enhance bone remodeling and mineral density through cytokine-mediated and endocrine mechanisms, including IL-6, IL-15, and irisin-dependent Wnt/β-catenin activation [108–110]. In skeletal muscle, exercise suppresses myostatin expression, promotes mitochondrial biogenesis, and stimulates muscle protein synthesis, effectively counteracting sarcopenia [108]. Numerous clinical studies also confirm that exercise is an effective intervention for age-related musculoskeletal diseases. First, aerobic and resistance exercise alleviate joint pain and improve function in OA, with comparable efficacy across training modalities [111]. Second, progressive resistance training increases bone mineral density and reduces fracture risk [112,113], while endurance and strength training improve mitochondrial function and muscle mass in aging populations [116,117]. Collectively, exercise represents a safe, cost-effective, and multifaceted intervention for age-related musculoskeletal diseases.

4.2. Exercise modulates the gut microbiota

Because the shared SCFA- and butyrate-related mechanisms, including barrier reinforcement, HDAC inhibition, Treg differentiation, and inflammatory control, have been described in the preceding gut-joint, gut-bone, and gut-muscle sections, this section focuses on exercise-specific evidence and avoids repeating those common pathways in detail.

In recent years, an increasing number of studies have shown that exercise can significantly regulate the composition and function of the gut microbiota. Accumulating evidence from both animal and human studies supports that exercise significantly alters gut microbial composition and function [61,118,119]. For example, moderate aerobic exercise increases α- and β-diversity, enriches beneficial taxa such as Bifidobacterium and Akkermansia, and enhances short-chain fatty acid production, particularly butyrate [120]. In this section, we discuss in detail the effects of exercise on the gut microbiota and the mechanisms by which it is regulated. Exercise affects the gut microbiota through various mechanisms, thereby having a positive impact on health.

4.2.1. The impact of exercise on the gut microbiota

Exercise exerts multidimensional effects on the gut microbiota by altering microbial diversity, taxonomic composition, and metabolic activity. A systematic review and meta-analysis reported that moderate exercise significantly increases the Shannon index, reflecting enhanced alpha diversity and improved microbial richness and evenness. These changes are generally accompanied by an increased abundance of beneficial bacteria, including Bifidobacterium, Lactobacillus, Faecalibacterium, and Akkermansia, alongside a reduction in taxa associated with sedentary behavior and metabolic dysfunction [120,121]. The effects of exercise on gut microbiota vary according to exercise modality and intensity. Moderate aerobic exercise consistently increases both α- and β-diversity and promotes the enrichment of beneficial taxa [122]. In contrast, high-intensity interval training (HIIT) may induce transient microbial perturbations, which often normalize with continued training; nevertheless, HIIT has also been associated with increases in specific beneficial bacteria such as Akkermansia [123]. Excessive or prolonged high-intensity exercise, however, may disrupt microbial homeostasis, increase inflammatory markers, and impair gut barrier integrity [124]. Beyond compositional changes, exercise influences host metabolic health by modulating microbial metabolic outputs. In particular, exercise increases the production of SCFAs, especially butyrate, which play key roles in lipid metabolism, immune regulation, and inflammation suppression. Exercise-induced alterations in bile acid profiles and tryptophan metabolism further contribute to metabolic homeostasis [120]. Conversely, overexertion has been associated with increased intestinal permeability and translocation of microbial-derived LPS, triggering systemic inflammatory responses characterized by elevated IL-6, IL-1β, TNF-α, and NF-κB signaling [125,126]. Studies in endurance athletes, such as marathon runners, further highlight that extreme training loads may substantially reshape gut microbiota structure [127].

Overall, these findings underscore the importance of individualized exercise prescriptions, emphasizing appropriate intensity and duration to maximize gut microbiota–mediated health benefits while minimizing adverse effects. The effects of exercise on the gut microbiota are summarized in Table 6.

Table 6.

Impact of exercise on gut microbiota.

Aspect	Key findings	Mechanisms	References
Diversity of gut microbiota	- Exercise increases the Shannon index, indicating enhanced alpha diversity. - Moderate exercise increases beneficial bacteria (e.g. Bifidobacterium, Lactobacillus) and reduces harmful bacteria (e.g. Bacteroidetes).	- Promotes richness and evenness of gut microbes. - Enhances the abundance of beneficial bacteria.	[120–122]
Exercise intensity and mode	- Moderate-intensity aerobic exercise increases α-diversity and β-diversity. - HIIT may cause short-term imbalance but increases Akkermansia and reduces Lactobacillus.	- Different exercise types and intensities have varying effects on microbial composition. - HIIT may temporarily disrupt microbial balance but promotes specific beneficial bacteria.	[122,123]
Metabolic effects	- Exercise increases SCFAs (e.g. butyrate), improving lipid metabolism, immune function, and reducing inflammation. - Regulates bile acid profiles and tryptophan metabolism.	- Enhances metabolic activities of gut microbiota. - Improves host metabolic state through microbial metabolites.	[124]
Negative effects of excessive exercise	- Prolonged high-intensity exercise may disrupt gut microbiota balance, increase inflammatory markers, and impair gut barrier function. - Excessive exercise increases intestinal permeability and systemic inflammation.	- Leads to intestinal barrier dysfunction and systemic inflammation via LPS and pro-inflammatory cytokines (e.g. IL-6, IL-1β, TNF-α, NF-κB).	[120,125,126]
Athlete-specific changes	- High-intensity athletes (e.g. marathon runners) show significant alterations in gut microbiota structure. - Changes in abundance of beneficial bacteria.	- Intense exercise may lead to unique microbial adaptations, potentially beneficial or harmful depending on context.	[127]

4.2.2. Mechanisms of gut microbiota regulation by exercise

Exercise modulates the gut microbiota through integrated neuroendocrine, immune, and intestinal barrier–related pathways. During physical activity, activation of the hypothalamic–pituitary–adrenal (HPA) axis and the autonomic nervous system leads to dynamic hormonal fluctuations that indirectly influence microbial composition and metabolism. For example, exercise-induced catecholamine release, such as norepinephrine, has been shown to affect microbial growth and metabolic activity [127]. In parallel, exercise stimulates enteroendocrine cells to secrete hormones including GLP-1 and PYY, which contribute to the regulation of intestinal barrier integrity and host–microbiota interactions [126,128,129].

In addition to neuroendocrine regulation, exercise exerts a profound immunomodulatory effect on the gut environment. Regular physical activity enhances intestinal mucosal immunity and attenuates chronic low-grade inflammation, thereby promoting microbial homeostasis [119]. At the mechanistic level, regular exercise enhances endogenous antioxidant defenses, reflected by increased activity of enzymes such as catalase and glutathione peroxidase, while simultaneously promoting the production of anti-inflammatory cytokines, notably IL-10. In parallel, exercise suppresses inflammatory signaling by downregulating pro-inflammatory mediators, including TNF-α and IL-17 [130,131].

Exercise further supports gut microbial stability by strengthening intestinal barrier function and reducing permeability. Moderate endurance exercise enhances antioxidant defenses within the gut epithelium and modulates tight junction–related proteins, such as zonulin and claudin-1, contributing to improved epithelial integrity [114]. Moreover, exercise-induced increases in SCFA production – particularly butyrate – provide metabolic support for colonocytes and reinforce barrier function, further stabilizing the gut ecosystem [119].

Beyond these molecular and cellular mechanisms, exercise promotes intestinal motility, optimizes nutrient availability for microbial fermentation, and alleviates psychological stress, all of which indirectly contribute to gut microbiota resilience. Collectively, these interconnected pathways highlight exercise as a potent modulator of gut microbial homeostasis. Having outlined these mechanisms, an important question arises: do exercise-induced microbial adaptations translate into clinically meaningful benefits for age-related musculoskeletal diseases? The regulatory mechanisms by which exercise modulates the gut microbiota are summarized in Table 7.

Table 7.

Mechanisms of gut microbiota regulation by exercise.

Aspect	Key findings	Mechanisms	References
Neuroendocrine pathways	- Exercise activates the HPA axis and autonomic nervous system, regulating hormone levels. - Hormonal changes (e.g. norepinephrine) affect gut microbiota growth and metabolism.	- Neuroendocrine changes indirectly influence microbial composition and metabolism. - Hormones like GLP-1 and PYY regulate intestinal barrier function.	[127–129]
Immune modulation	- Exercise enhances mucosal immune function, reduces inflammation, and maintains microbial balance. - Increases antioxidant enzymes (e.g. CAT, GSH-Px) and anti-inflammatory cytokines (e.g. IL-10).	- Improves immune activity in the gut, reducing pro-inflammatory cytokines (e.g. TNF-α, IL-17) and promoting anti-inflammatory responses.	[119,130,131]
Gut barrier function	- Exercise improves intestinal barrier function and reduces permeability. - Increases antioxidant enzymes (e.g. SOD2, catalase) and tight junction proteins (e.g. zonulin, claudin 1).	- Enhances intestinal barrier integrity through antioxidant activity and tight junction regulation. - Increases butyrate production, supporting intestinal cell energy and barrier maintenance.	[114,119]
Additional mechanisms	- Exercise promotes intestinal motility and improves digestive function. - Alleviates psychological and physiological stress, contributing to microbial stability.	- Provides a better nutritional environment for gut microbiota. - Reduces stress-related disruptions to microbial balance.	[119,130]

4.3. Exercise-induced changes in gut microbiota improve age-related musculoskeletal diseases

Accumulating evidence suggests that exercise-induced modulation of the gut microbiota translates into functional benefits in major age-related musculoskeletal conditions, including OA, OP, and sarcopenia. Building on the dysbiosis observed in these disorders and the regulatory effects of exercise on both the gut ecosystem and the musculoskeletal system, the gut microbiota has emerged as a critical intermediary linking physical activity to skeletal and muscle health.

4.3.1. Osteoarthritis

Exercise improves OA partly by reshaping the gut microbiota and reducing microbiota-derived inflammatory mediators. In a high-fat diet–induced OA model, Li et al. demonstrated that voluntary wheel running restored microbial diversity, reduced endotoxin-producing bacteria, and lowered circulating and synovial LPS levels, thereby attenuating Toll-like receptor 4(TLR4) signaling, matrix metalloproteinase-13(MMP-13) expression, and cartilage degeneration [10]. These findings support a microbiota-mediated mechanism through which moderate exercise counteracts obesity-related OA progression.

Beyond aerobic exercise, other physical interventions appear to converge on similar gut-immune pathways. Clinical studies indicate that structured physical therapy alters gut microbial composition, with increased abundance of anti-inflammatory taxa such as Faecalibacterium, which correlates with improved muscle strength and reduced interleukin-6 levels in patients with OA [115]. Likewise, whole-body vibration has been shown to enhance regulatory T-cell differentiation and increase Lactobacillus abundance, promoting interleukin-10–mediated immune tolerance and reducing low-grade inflammation implicated in OA pathogenesis [132,133]. Notably, combining exercise with dietary interventions further amplifies these benefits. In obese rodent models, aerobic exercise combined with prebiotic supplementation synergistically restored beneficial microbes and completely prevented OA-like joint damage, underscoring the therapeutic potential of integrated lifestyle strategies [63].

4.3.2. Osteoporosis

Exercise also exerts protective effects against OP through gut microbiota–derived metabolic signaling. In diet-induced bone loss models, voluntary exercise normalized the Firmicutes/Bacteroidetes ratio, which is negatively associated with trabecular bone volume, thereby mitigating bone marrow adiposity and bone loss [134]. In addition, exercise enhances bile acid metabolism, as evidenced by increased fecal bile acid excretion in physically active mice [47,135–137]. Collectively, these findings suggest that exercise-induced microbial and bile acid remodeling represents a key mechanism underlying skeletal protection.

4.3.3. Sarcopenia

The beneficial effects of exercise on sarcopenia are closely linked to gut microbiota-derived SCFAs. Exercise consistently increases fecal SCFA concentrations, particularly in metabolically healthy individuals [106]. SCFAs, such as butyrate and acetate, serve as critical mediators of the gut-muscle axis by enhancing intestinal barrier integrity, reducing systemic inflammation, and directly regulating skeletal muscle metabolism. These metabolites promote mitochondrial energy production, improve insulin sensitivity, and suppress TNF-α- and NLRP3-mediated inflammatory signaling, thereby favoring anabolic processes in muscle tissue [138,139]. Conversely, reduced SCFA production is a hallmark of dysbiosis-associated muscle atrophy, highlighting the importance of microbiota-derived metabolites in maintaining muscle mass and function during aging [47]. Together, these observations suggest a plausible but still indirect pathway by which exercise may alleviate sarcopenia through restoration of microbial metabolic capacity and SCFA-related signaling. However, direct causal evidence linking exercise-induced increases in SCFAs to improved muscle function remains limited, and this pathway should therefore be interpreted as a mechanistic hypothesis requiring further validation.

Exercise, as a non-pharmacological intervention, can effectively improve age-related musculoskeletal diseases by modulating the diversity and function of the gut microbiota. However, due to insufficient direct evidence, further research is needed to determine the direct relationships among them (Figure 2).

Figure 2.

Exercise modulates the gut‑musculoskeletal axis through neuroendocrine, immune, antioxidant, and intestinal barrier pathways. These effects reshape microbial composition, enrich beneficial genera such as Bifidobacterium, Lactobacillus, Faecalibacterium, and Akkermansia, and increase bioactive metabolites including short‑chain fatty acids and bile acids. Together, these changes support bone homeostasis, joint protection, and muscle integrity, highlighting exercise as a potential intervention for osteoarthritis, osteoporosis, and sarcopenia.

4.4. Discussion: the ‘optimal dose’ of exercise and elucidating microbiome-mediated mechanisms

Although the beneficial effects of exercise on the gut microbiota and musculoskeletal system are well documented, considerable uncertainty remains regarding the optimal exercise strategies required to achieve these outcomes. Evidence summarized in this review suggests that the relationship between exercise intensity and microbiome modulation may follow an inverted U-shaped pattern, whereby moderate levels of physical activity enhance the abundance of beneficial bacterial taxa and increase short-chain fatty acid production, whereas excessive or prolonged high-intensity exercise may impair intestinal barrier function and promote inflammatory responses. These observations highlight the need for more precise quantification of exercise prescriptions; however, clearly defined parameters regarding exercise type, intensity, and frequency tailored to specific age groups and disease conditions remain insufficiently established.

More critically, the mechanistic links connecting exercise, gut microbiota alterations, and downstream health outcomes require further clarification. While existing studies frequently report associations between physical activity, microbial shifts, and improved health indices, the causal pathways underlying these relationships remain incompletely understood. Exercise-induced physiological perturbations, including changes in hormonal signaling, bile acid metabolism, and lactate production, may play a key role in shaping gut microbial composition, yet their specific contributions remain unclear. Likewise, the mechanisms by which microbiota-derived metabolites, such as SCFAs and secondary bile acids, cross biological barriers to influence distant target cells, including joint chondrocytes, osteoblasts, and skeletal muscle cells, warrant further investigation. Longitudinal studies incorporating multi-omics approaches, including metagenomic, metabolomic, and proteomic analyses conducted before and after structured exercise interventions, will be essential to delineate these causal pathways with greater precision.

5. Diet–exercise–microbiota synergy: an integrative mechanistic hypothesis

Accumulating evidence suggests that diet and exercise exert mutually reinforcing effects on musculoskeletal aging through convergent regulation of the gut microbiota. Unlike prior studies that treated diet and exercise as independent modulators of the gut microbiota, we propose a diet–exercise–microbiota synergy model that highlights bidirectional, reinforcing interactions. In this model, exercise enhances the microbiota’s responsiveness to dietary inputs by increasing microbial diversity, accelerating intestinal transit, and improving gut barrier function, thereby facilitating more efficient microbial adaptation to nutritional substrates. Conversely, diet supplies critical fermentable fibers, polyphenols, and lipids that support microbial synthesis of SCFAs, phenolic metabolites, and secondary bile acids, which in turn regulate bone remodeling, cartilage inflammation, and mitochondrial function in skeletal muscle. This framework goes beyond summarizing fragmented observations and offers a testable hypothesis: combined lifestyle interventions may produce greater musculoskeletal benefits than either intervention alone, and these effects are mediated by specific microbial metabolic pathways. We propose a diet–exercise–microbiota synergy model, whereby both interventions reshape microbial composition and function, thereby modulating metabolic and immune pathways along the gut–bone, gut–muscle, and gut–joint axis.

A key element of this model is that exercise may enhance the microbiota’s responsiveness to dietary inputs, reflected by increased microbial diversity, elevated SCFA production, and accelerated intestinal transit, collectively facilitating more efficient microbial adaptation to nutritional substrates [61]. In parallel, diet supplies critical substrates – including fermentable fibers, polyphenols, and lipids – that support microbial synthesis of SCFAs, phenolic metabolites, and secondary bile acids [140], which are known to regulate bone remodeling, cartilage inflammation, and mitochondrial function in skeletal muscle.

These reciprocal effects generate a reinforcing loop, in which dietary modulation optimizes microbial metabolic capacity while exercise improves ecological resilience and host–microbe signaling. This framework helps explain why combined lifestyle interventions, such as prebiotics plus aerobic training, confer superior protection against OA progression and diet-induced bone loss compared with either intervention alone [63]. Conceptualizing the microbiota as an integrative hub linking diet and exercise may therefore inform the development of more precise, multimodal strategies for musculoskeletal health.

Despite growing interest, several limitations hinder the translation of findings into clinical practice. First, heterogeneity of interventions (e.g. variable definitions of KDs, intermittent fasting protocols, exercise types and intensities) makes cross-study comparison difficult. Second, causality remains unclear: most studies report associations between microbial shifts and health outcomes, but few use fecal microbiota transplantation, germ-free models, or controlled metabolite supplementation to establish causation. Third, translational barriers persist, as animal microbiomes differ substantially from humans, and long-term human trials are scarce. Fourth, individual variability in baseline microbiota, genetics, and lifestyle is rarely accounted for, limiting the development of personalized strategies. Addressing these gaps will require standardized protocols, multi-omics longitudinal studies, and mechanism-driven intervention designs.

6. Future promising directions for anti-aging

The collective evidence underscores that both diet and exercise can influence musculoskeletal health via the gut microbiota. However, the field is moving beyond isolated interventions towards a more integrated and personalized future. The most promising directions lie in leveraging these interactions for precision medicine.

6.1. Precision nutrition targeting the gut microbiome

Precision nutrition aims to tailor dietary interventions based on individual-specific features, including microbiome composition, genetic background, metabolic status, and lifestyle factors, to optimize health outcomes and delay aging [141,142]. In the context of aging, this approach emphasizes identifying microbiome-driven nutritional needs and selectively modulating microbial functions through targeted dietary components, probiotics, or prebiotics [143].

Rather than generalized dietary recommendations, future strategies will focus on aligning dietary patterns with an individual’s microbial functional capacity to promote metabolic resilience and immune homeostasis. Dietary components with antioxidant and anti-inflammatory properties, such as polyphenols, as well as macronutrient-modified regimens, have demonstrated potential to modulate inflammatory signaling, immune aging, and systemic metabolic pathways [144–149].

With advances in multi-omics profiling and artificial intelligence–assisted analytics, dynamic monitoring of microbiome responses may enable real-time adjustment of personalized nutritional strategies, thereby delaying the onset and progression of aging-related diseases [150].

6.2. Exercise mimetics and caloric restriction mimetics

Exercise mimetics and caloric restriction mimetics (CRMs) represent pharmacological strategies designed to reproduce key molecular benefits of physical activity or energy restriction, particularly in populations unable to sustain long-term lifestyle interventions. Exercise mimetics target pathways involved in mitochondrial biogenesis, muscle fiber remodeling, and metabolic regulation, including AMPK and sirtuin signaling [151,152]. CRMs, such as rapamycin, metformin, resveratrol, and glucosamine, act through complementary mechanisms involving mTOR inhibition, AMPK activation, and autophagy induction [153–156].

Although these agents show promise in extending healthspan in experimental models, their long-term safety, tissue specificity, and interaction with endogenous microbiome-host signaling remain insufficiently understood. Future research should clarify whether these mimetics synergize with – or disrupt – microbiome-mediated adaptations to diet and exercise, which will be critical for their rational integration into anti-aging strategies.

6.3. Integrated interventions and multi-omics driven personalization

Future research should move beyond examining diet or exercise in isolation and explore their synergistic effects. For instance, can regular exercise enhance an individual’s response to FMD or probiotic supplementation? Designing RCTs on combined ‘diet-exercise’ interventions and utilizing machine learning models to analyze multi-omics data could help identify biomarkers and patient subtypes that respond best to specific combination strategies.

6.4. From correlation to causation: Next-Generation tools for mechanistic research

Establishing causality in microbiome-mediated aging requires next-generation experimental platforms. Humanized microbiota mouse models colonized with patient-derived communities provide controlled systems to test causal effects of diet and exercise interventions. In parallel, targeted genetic manipulation of microbial pathways using CRISPR-based tools enables functional validation of specific metabolites and signaling axes. The development of controlled-release formulations of microbiome-derived metabolites further offers a translational avenue to directly assess therapeutic efficacy.

6.5. Focusing on microbiome-immune-stem cell interactions in the aging niche

Musculoskeletal aging is characterized by stem cell exhaustion and immune dysfunction. An emerging frontier is the investigation of how gut microbiota–derived signals influence mesenchymal stem cells, muscle satellite cells, and the local immune microenvironment within bone and muscle. Deciphering this microbiome–immune–stem cell axis may reveal fundamental cellular mechanisms underlying the gut–bone and gut–muscle connections and identify novel targets for regenerative anti-aging interventions.

7. Conclusions and outlook

Overall, the available evidence partially supports the proposed diet–exercise–microbiota synergy model; however, the evidence is predominantly preclinical and associative, and causal effects in humans remain unconfirmed. This review has explored how anti-aging diets and exercise influence age-related musculoskeletal diseases through modulation of the gut microbiota. Accumulating evidence indicates that the gut microbiota plays a critical role in human aging, with dysbiosis closely linked to the pathogenesis of various musculoskeletal disorders. Anti-aging dietary strategies – such as caloric restriction and isocaloric nutrient restriction – along with moderate exercise, can significantly reshape the gut microbiota, thereby exerting beneficial effects on bone and muscle health. These interventions not only improve gut microbial ecology but also enhance metabolic homeostasis and mechanical integrity via the gut-joint, gut-bone, and gut-muscle axis, thereby reducing the risk of OP, OA, and sarcopenia.

Nevertheless, several limitations persist in current research. Most studies are based on animal models or small-scale human trials, which restricts the generalizability of the findings. The precise molecular mechanisms underlying the gut-bone/muscle axis remain incompletely elucidated, and causal relationships have yet to be firmly established. Significant inter-individual variability in gut microbiota composition and host responses is often overlooked in intervention studies. Moreover, there is a lack of standardized protocols regarding dietary composition, exercise type and intensity, and a scarcity of long-term, large-scale clinical trials. Finally, research on the synergistic effects of combined diet and exercise interventions is still in its early stages.

Looking ahead, future research should prioritize the following directions: elucidating specific mechanisms through rigorously designed basic research; conducting large-scale, long-term clinical trials to validate intervention efficacy; and developing personalized strategies tailored to individual gut microbiota profiles, genetic backgrounds, and lifestyle factors.

Interdisciplinary collaboration will be essential to translate these findings into effective clinical practices for promoting healthy aging.

Funding Statement

No funding was received for this work.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no data were created or analysed in this research.