Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, represents a significant global health concern affecting approximately 10% of older adults worldwide (1, 2). Recognized as a geriatric syndrome with substantial clinical implications, sarcopenia contributes to increased risk of falls, functional decline, disability, poor quality of life, and premature mortality (3, 4). The European Working Group on Sarcopenia in Older People 2 (EWGSOP2) diagnostic algorithm defines sarcopenia through the concurrent presence of reduced muscle strength and diminished skeletal muscle mass, with severe sarcopenia further characterized by impaired physical performance (5). While age-related physiological changes remain the primary driver of sarcopenia development, growing evidence suggests that various modifiable and non-modifiable factors—including chronic inflammation, metabolic disorders, malnutrition, and genetic predisposition—significantly influence its pathogenesis (6, 7).

In recent years, increasing attention has focused on the potential role of infectious agents, particularly viruses with persistent or latent infection profiles, in age-related degenerative conditions (8, 9). Human herpesvirus 6 (HHV-6), a ubiquitous beta-herpesvirus with a high global seroprevalence exceeding 90% in adults, exhibits distinct biological characteristics that may have implications for chronic health conditions (10). HHV-6 exists in two closely related variants (HHV-6A and HHV-6B) and demonstrates unique genomic integration capabilities, with approximately 1% of the population carrying chromosomally integrated HHV-6 (ciHHV-6) (11, 12). This integration can manifest as different molecular phenotypes, including “typical positive” (with integration of both the direct repeat [DR] and unique [U] regions) and “DR-only positive” (with selective integration or amplification of DR sequences) (13, 14).

Chronic viral infections may contribute to sarcopenia pathophysiology through several biological mechanisms. Persistent viral presence can induce sustained low-grade inflammation, characterized by elevated pro-inflammatory cytokines (IL-6, TNF-α) that promote protein catabolism and impair muscle regeneration (15). Viral infections may also accelerate cellular senescence processes through oxidative stress pathways and telomere attrition, potentially connecting viral burden with accelerated biological aging (16, 17). HHV-6, specifically, has been associated with altered immune function, systemic inflammation, and tissue-specific pathologies that could theoretically influence muscle homeostasis (18, 19). Furthermore, emerging evidence suggests sex-specific differences in both viral immune responses and sarcopenia manifestation, highlighting the importance of gender-stratified analyses in investigating such associations (20, 21).

Despite these potential mechanistic links, the relationship between HHV-6 infection status and sarcopenia remains largely unexplored. Previous investigations have examined associations between cytomegalovirus (another herpesvirus) seropositivity and frailty or physical function (22), but specific studies addressing HHV-6 and skeletal muscle health are notably absent from the literature. Additionally, the potential modifying effects of important biological factors—such as systemic inflammation, body composition, genetic susceptibility, and telomere length—on virus-mediated muscle pathology have not been adequately characterized (23, 24).

Given these knowledge gaps, this study aimed to comprehensively investigate the association between HHV-6 status and sarcopenia using the UK Biobank cohort. Specifically, we sought to: 1) determine whether different HHV-6 integration profiles are associated with sarcopenia risk; 2) explore potential sex-specific differences in these associations; 3) examine the modifying effects of biological factors including inflammation markers, body mass index, genetic predisposition, and telomere length; and 4) establish temporal relationships through both cross-sectional and longitudinal analyses. By elucidating these relationships, this study contributes to the growing understanding of potential infectious determinants of sarcopenia and may inform future preventive and therapeutic strategies.

This study provides novel evidence of a significant association between HHV-6 status and sarcopenia risk, with distinctive patterns observed across different viral integration profiles and between sexes. Our findings demonstrate that individuals with DR-only positive HHV-6 status exhibited nearly fourfold higher odds of sarcopenia at baseline and approximately fivefold elevated risk during follow-up after comprehensive adjustment for confounding factors. Notably, these associations were predominantly driven by pronounced effects in males, where DR-only positivity conferred over fivefold increased sarcopenia risk, while females showed significant associations only with typical positive status. Furthermore, telomere length significantly modified the HHV-6-sarcopenia relationship, with distinct interaction patterns observed between sexes.

The observed association between HHV-6 DR-only positive status and sarcopenia represents a novel finding in the field of muscle health. Previous investigations have primarily focused on CMV in relation to physical function and frailty (29, 30), with limited attention to other herpesviruses. Wang et al. demonstrated that CMV seropositivity was associated with increased frailty risk in older people (22), while Matheï et al. reported associations between CMV infection and inflammatory markers linked to physical decline (31). Our results extend this emerging field by identifying HHV-6, particularly the DR-only phenotype, as a potential viral determinant of muscle health. The selective association with DR-only positivity, rather than typical positive status, suggests that specific molecular mechanisms related to partial viral genome integration may contribute to muscle pathology.

The marked sexual dimorphism observed in our analyses aligns with growing evidence of sex-specific immunological responses to viral infections (32, 33). The pronounced association between DR-only positivity and sarcopenia in males may reflect sex-based differences in immune responses to latent viral infections. Testosterone has been shown to modulate pro-inflammatory cytokine production (34), potentially exacerbating muscle catabolism in the presence of persistent viral triggers. Conversely, the female-specific association with typical positive status suggests distinct pathophysiological pathways. Estrogen’s immunomodulatory effects may alter viral reactivation patterns (35), triggering different inflammatory cascades associated with complete viral integration. These findings underscore the importance of sex-stratified analyses in investigations of infectious determinants of age-related conditions.

Particularly intriguing was the interaction between telomere length and HHV-6 status in modifying sarcopenia risk. In males, DR-only positivity conferred elevated sarcopenia risk regardless of telomere length, though the effect was slightly more pronounced among those with longer telomeres. This counterintuitive finding challenges the traditional view that shorter telomeres, typically associated with cellular senescence and aging (36), would exacerbate pathological processes. One potential explanation involves the relationship between telomere biology and viral integration. HHV-6 demonstrates a unique tropism for telomeric regions (37, 38), potentially disrupting telomere function even when length appears preserved. Michael L Wood et al. found that HHV-6 integration can lead to telomere lengthening at DRL-T2 (39). The HHV-6 genome can be excised and reactivated in this manner. Therefore, the DR-only group may represent those with reactivation. Furthermore, viral integration into telomeric regions may impair the recruitment of telomere-associated proteins necessary for proper telomere maintenance (40), creating functional deficits independent of measured length. However, measured telomere length reflects only one aspect of telomere biology, and the association reported here is observational and does not establish causation. These observed interactions may reflect an underlying confounding factor or biological synergy that has yet to be identified.

The biological mechanisms underlying the observed associations likely involve complex interactions between viral persistence, inflammation, and muscle homeostasis. DR-only positivity, representing selective integration or amplification of direct repeat viral sequences, may disrupt host genomic stability through insertional mutagenesis (41, 42). Such genomic alterations could potentially affect genes involved in myogenesis or muscle protein synthesis. Additionally, viral integration may trigger chronic low-grade inflammation—a well-established contributor to sarcopenia pathogenesis (43). HHV-6 has been shown to induce pro-inflammatory cytokines including IL-6 and TNF-α (44), which promote protein catabolism and impair muscle regeneration. The sex-specific patterns observed may reflect differential inflammatory responses, with males typically exhibiting more pronounced pro-inflammatory profiles following immune challenges (29, 45).

Mitochondrial dysfunction represents another potential mechanistic link between HHV-6 and sarcopenia. HHV-6 proteins have been shown to localize within mitochondria, altering respiratory function and promoting oxidative stress (46, 47). Mitochondrial impairment is increasingly recognized as a central feature of sarcopenia (48), potentially explaining how viral integration contributes to muscle deterioration. Furthermore, cellular senescence, a biological process characterized by irreversible cell cycle arrest and pro-inflammatory secretory phenotype, may be accelerated by chronic viral presence (49), contributing to impaired satellite cell function and compromised muscle regenerative capacity.

While no significant associations were found between EBV/CMV serostatus and sarcopenia in our cohort (both p>0.05), these results must be interpreted with caution. Small subgroup sizes (n=33) led to extremely wide confidence intervals, severely limiting statistical power to detect modest effects. Consequently, we cannot conclusively rule out confounding or effect modification by these viruses. Previous studies suggest immunosenescence may be associated with reduced muscle mass and strength, but direct evidence establishing its causal relationship with sarcopenia remains limited and requires further investigation (50).

Our study has several strengths, including its large sample size, prospective design, and comprehensive assessment of potential confounding and modifying factors. The use of standardized sarcopenia definitions following EWGSOP2 criteria enhances the clinical relevance of our findings. Additionally, the application of sensitive detection methods for HHV-6 status allowed for differentiation between integration profiles, revealing associations that might have been missed in studies examining only viral serostatus. The consistent results across sensitivity analyses using alternative sarcopenia definitions further supports the robustness of our findings.

However, several limitations warrant consideration. First, despite adjustment for numerous covariates, residual confounding cannot be entirely excluded. Second, the predominantly Caucasian (>95%) UK Biobank population limits generalizability to other ethnic groups. While valuable for investigating within-population effects, results derived from such a homogeneous cohort cannot be assumed to translate directly to populations of different ancestral backgrounds or diverse ethnic groups. Future large-scale, intentionally diverse cohorts are needed to validate or refute these findings across globally representative populations. Third, while our follow-up analyses support temporal relationships, the observational nature of the study precludes definitive causal inferences. Fourth, our classification of HHV-6 status relied on predetermined ΔCt thresholds established by the UK Biobank; however, these thresholds lack independent validation in external cohorts. Furthermore, the absence of a universal gold-standard diagnostic criterion for iciHHV-6 detection may introduce potential misclassification bias. Finally, the relatively small number of DR-only positive cases, particularly in sex-stratified analyses, resulted in wide confidence intervals despite statistical significance. The observed effect size must therefore be interpreted with caution, as it may represent an exaggeration of the true association. Future studies with larger, adequately powered DR-only cohorts are essential to provide more reliable estimates.

The clinical implications of our findings are substantial. Identification of HHV-6 status, particularly DR-only positivity in males, may enhance risk stratification for sarcopenia development. This could facilitate targeted preventive interventions in high-risk individuals, potentially including anti-inflammatory approaches or specific exercise regimens. From a therapeutic perspective, our results raise the possibility that antiviral strategies might benefit select sarcopenia patients with evidence of HHV-6 integration, though this requires formal investigation. Furthermore, the interaction with telomere biology suggests potential value in combined approaches addressing both viral burden and cellular senescence processes.

Future research directions should include mechanistic studies investigating HHV-6 effects on myocyte function, satellite cell activity, and muscle regeneration. Larger prospective cohorts with repeated measures of both HHV-6 status and muscle parameters would enhance understanding of temporal relationships. Studies incorporating viral reactivation markers alongside integration status would provide insights into active versus latent infection effects. Additionally, interventional trials targeting inflammation in HHV-6 positive individuals at risk for sarcopenia could evaluate potential preventive approaches.

In conclusion, this study provides novel evidence linking HHV-6 status, particularly DR-only positivity, with increased sarcopenia risk in a sex-specific manner, with males showing pronounced vulnerability. These associations are further modified by telomere length, suggesting complex interactions between viral integration, cellular senescence, and muscle health. Our findings contribute to the emerging understanding of infectious determinants of age-related muscle deterioration and may inform future preventive and therapeutic strategies for sarcopenia.