Interventions and Opportunities to Enhance Aging Among People With HIV: A Focus on Frailty, Sarcopenia, and Intrinsic Capacity

Abstract

Antiretroviral therapy has transformed HIV into a chronic condition, resulting in a growing population of older people with HIV (PWH). This shift has been accompanied by an increased burden of age-related conditions, including frailty and sarcopenia, that compromise physical function and quality of life. Frailty and sarcopenia arise from complex biologic processes, many of which may be amplified in PWH. Recent conceptual advances emphasize intrinsic capacity (the composite of physical and mental capacities that determine functional ability) as a framework for understanding aging-related vulnerability. Emerging evidence suggests that social and structural determinants influence trajectories of intrinsic capacity and contribute to disparities in frailty risk. Geriatric-informed care models, including comprehensive geriatric assessment and the Integrated Care for Older People framework set forth by the World Health Organization, offer structured approaches to identify early declines in intrinsic capacity and guide individualized interventions. Exercise, nutrition optimization, and multidisciplinary care remain foundational strategies to mitigate frailty and sarcopenia, and emerging pharmacologic approaches targeting inflammation and metabolic dysfunction may influence aging trajectories. Integrating intrinsic capacity into HIV care may improve risk stratification and support interventions aimed at preserving function and healthy aging among PWH.

Introduction

The widespread access and use of effective antiretroviral therapy (ART) have transformed HIV from a fatal infection to a chronic condition, increasing the life expectancy of people with HIV (PWH). As a result, the proportion of PWH aged 50 years and older has grown substantially. This demographic shift has been accompanied by an increased burden of age-associated conditions and geriatric syndromes, such as frailty and sarcopenia, that compromise functional ability and quality of life among older PWH.¹

Frailty is an age-related syndrome characterized by increased vulnerability to stressors, resulting from diminished physiologic reserves and resilience.¹ In PWH, frailty occurs at relatively younger ages and is associated with adverse outcomes, including falls, hospitalization, disability, and mortality.² Despite varying operational definitions, studies using established measures, such as the Fried phenotype, demonstrate that a substantial subset of older PWH meet the criteria for frailty and prefrailty.³

Sarcopenia, the progressive loss of skeletal muscle mass and strength, is closely related to frailty and functional decline.^4,5 In PWH, sarcopenia has been observed across diverse cohorts, with prevalence estimates shaped by diagnostic criteria such as those proposed by the EW-GSOP2 (European Working Group on Sarcopenia in Older People).⁴ Sarcopenia correlates with traditional frailty measures and is associated with lower body mass index, advanced age, poorer immune status, and worse physical performance.⁶

Although frailty and sarcopenia have been recognized for decades within geriatric medicine, recent concepts expand on these specific syndromes to emphasize intrinsic capacity, the composite of an individual's physical, cognitive, psychologic, sensory, and vitality capacities, as a framework to promote healthy aging.⁷·⁸ The intrinsic capacity framework, introduced by the World Health Organization (WHO), advocates shifting from a disease-centered to a function-oriented paradigm in aging care. Within this model, declines in intrinsic capacity precede and contribute to frailty and disability, and may provide early signals for targeted prevention and intervention.^9–11

There is a growing interest in the holistic concept of intrinsic capacity among older PWH.^9–11 Novel studies are beginning to incorporate intrinsic capacity across clinical care and research, investigating links to mechanisms, correlation with other measures, and the impact of interventions, highlighting the promise of intrinsic capacity as an integrative marker in HIV aging clinical care and research (Figure).¹⁰

Figure.

Intrinsic Capacity, Frailty, and Sarcopenia in Aging With HIV: Biologic Drivers, Social Determinants, and Care Strategies. This figure illustrates how biologic mechanisms and social and structural determinants influence the 5 domains of intrinsic capacity (vitality, locomotion, sensory function, psychologic health, and cognition) in older people with HIV. Declines across these domains increase vulnerability to frailty and sarcopenia, leading to reduced physical function, disability, and poorer quality of life. Integrated care strategies, including comprehensive geriatric assessment, exercise and nutrition interventions, and selected pharmacologic therapies, aim to identify early declines and preserve intrinsic capacity to support healthy aging.

Mechanisms Underlying Frailty, Sarcopenia, and Diminished Intrinsic Capacity

Frailty and sarcopenia are interrelated syndromes that arise from cumulative declines in physiologic reserve, with sarcopenia representing a key component of physical frailty.¹² However, rather than viewing these conditions solely through a mechanistic lens, newer geroscience and geriatric care models increasingly situate them within the broader construct of intrinsic capacity.⁷ In this framework, biologic processes linked to frailty and sarcopenia (including mitochondrial dysfunction, cellular senescence, impaired proteostasis, chronic inflammation, inadequate nutrition, metabolic dysregulation, and physical inactivity) can be understood as drivers of decline in intrinsic capacity domains, particularly locomotion and vitality.¹² In PWH, persistent immune activation, chronic inflammation, and viral coinfections may further accelerate these pathways, contributing to functional vulnerability even in the absence of overt muscle loss.¹³ Emerging evidence suggests that lower intrinsic capacity scores are associated with frailty, impaired instrumental activities of daily living, worse patient-reported outcomes, and the presence of inflammatory biomarkers.¹⁴These findings support intrinsic capacity as a function-centered framework that integrates biologic, clinical, and contextual drivers of aging-related vulnerability. Integrating biomarkers with objective functional assessments and intrinsic capacity measures may therefore improve risk stratification and guide interventions aimed at preserving function and healthy aging in PWH.

Demographic and Social Determinants of Frailty, Sarcopenia, and Intrinsic Capacity

Social and structural inequities substantially shape frailty risk among PWH. Housing instability, including unstable housing and homelessness, is strongly associated with more than twice the prevalence of frailty among adults in HIV care, even among younger individuals and those who are virally suppressed.¹⁵ This highlights how socioeconomic precarity can accelerate aging-related vulnerability independent of traditional clinical factors.

Food insecurity is a crucial structural determinant influencing frailty risk. Emerging data among aging PWH in the US demonstrate that food insecurity and undernutrition are highly prevalent and strongly associated with impaired physical function and frailty-related outcomes, including poorer short physical performance battery scores, impaired balance, slower chair-rise time, and weight loss.¹⁶ Consistent with these results, a large multicohort study of more than 3000 PWH from CNICS (Center for AIDS Research [CFAR] Network of Integrated Clinical Systems) and MASH (the Miami Adult Studies on HIV) found that food insecurity was associated with increasing frailty severity, with individuals experiencing low or very low food security having significantly higher odds of being prefrail or frail.¹⁷ In addition, neighborhood disadvantage (measured by the Area Deprivation Index) has been linked to lower physical activity levels, a key frailty component, even though overall frailty prevalence did not differ by neighborhood status.¹⁸

Epidemiologic studies from sub-Saharan Africa and Latin America underscore the heterogeneity of aging with HIV across contexts. Recent work suggests that frailty prevalence and its correlates in older African cohorts may differ from those observed in high-income settings, likely reflecting variations in HIV epidemiology, comorbidity profiles, type of employment (physically demanding vs sedentary), and social determinants of health.¹⁹ Similarly, sociocultural factors and genetic diversity in Latin America and the Caribbean play a crucial role in shaping aging-related outcomes and are essential considerations for optimizing the management of chronic comorbidities among PWH in these settings.²⁰

Together, these findings suggest that structural determinants, such as context, housing instability, food insecurity, and neighborhood disadvantage, may contribute to aging-related vulnerability among PWH by shaping trajectories of intrinsic capacity, particularly in domains such as locomotion and vitality that are closely linked to frailty and physical function. Framing these disparities within an intrinsic capacity perspective provides a more integrative understanding of how biologic, clinical, and social factors interact to influence functional aging in PWH.

Nondrug Interventions

Nondrug interventions to prevent and mitigate frailty and sarcopenia in older PWH are increasingly framed within geriatric-informed models of care that emphasize preservation of intrinsic capacity.²¹ Traditional HIV-centric care models often fail to adequately address age-related functional decline, multimorbidity, and geriatric syndromes such as frailty and sarcopenia. Perspectives from geriatric and HIV specialists underscore the need for coordinated multidisciplinary approaches that integrate physical function, nutrition, mental health, and social vulnerability into routine HIV care for older adults.²¹

In this context, the WHO Integrated Care for Older People (ICOPE) framework provides a care-delivery model to operationalize intrinsic capacity in clinical and community settings.²² The ICOPE approach emphasizes early screening for declines across intrinsic capacity domains, followed by person-centered assessment and targeted interventions aimed at preserving functional ability.²² Comprehensive geriatric assessment (CGA) and structured geriatric screening closely align with this model and represent strategies for identifying deficits in intrinsic capacity and guiding individualized nondrug interventions. Feasibility trials of CGA in frail older PWH demonstrate acceptability and potential benefits in identifying actionable targets, such as physical inactivity, poor nutrition, polypharmacy, and psychosocial needs, that directly contribute to frailty and sarcopenia risk.^23,24

Within these integrated care frameworks, exercise and lifestyle interventions (including nutrition) are foundational to addressing sarcopenia and functional decline in older PWH.²⁵ Resistance and multicomponent exercise programs are key interventions to improve muscle strength, mobility, and physical performance, particularly when embedded in multidisciplinary care pathways informed by geriatric screening or CGA.²⁶ Recent evidence from clinical trials demonstrates that structured exercise interventions improve a number of domains of physical function, frailty, and body composition among older PWH. In the HEALTH (High-Intensity Exercise to Attenuate Limitations and Train Habits in Older Adults With HIV) randomized trial, high-intensity interval training and continuous moderate-intensity exercise combined with resistance training significantly improved functional outcomes (400-m walk performance and muscle strength) among sedentary PWH aged 50 years and older, with no meaningful differences between exercise modalities.²⁷ These findings suggest that different aerobic exercise strategies can effectively improve physical function, allowing programs to be tailored to individual preferences to enhance adherence. Additional analyses from the same trial demonstrated that exercise reduced the prevalence of prefrailty and frailty and was associated with modest improvements in sarcopenia prevalence, with larger gains in functional performance observed among participants who were prefrail or frail at baseline.²⁸

Additional mechanistic findings from the HEALTH trial provide insight into the biologic effects of exercise in older PWH. In a molecular substudy, Sun and colleagues examined changes in skeletal muscle DNA methylation and epigenetic age following the same 16-week exercise intervention.²⁹ Exercise was associated with widespread changes in DNA methylation across pathways related to neural development, endocrine signaling, and cellular repair. Although changes in muscle epigenetic age clocks were modest, these results suggest that exercise may influence molecular processes involved in muscle aging and resilience.²⁹ Together with the functional improvements observed in the HEALTH trial, these findings support exercise as a key nondrug strategy to promote intrinsic capacity domains of locomotion and vitality, and mitigate frailty and sarcopenia in aging PWH.

Longer-term exercise programs demonstrate benefits for sarcopenia-related outcomes. In the GYM (Grow Your Muscle) randomized trial, a 48-week home-based physical activity intervention supported by a smartphone application substantially improved muscle strength, appendicular skeletal muscle mass, and lean body mass among PWH aged 50 years and older with sarcopenia compared with controls.³⁰ These findings highlight the feasibility of scalable, digitally supported exercise programs that can improve muscle health and body composition, and potentially expanding access to physical activity interventions for older PWH.³⁰

Nutritional status can be considered a component of intrinsic capacity and a driver of intrinsic capacity. Nutritional optimization, especially adequate protein intake and micronutrient sufficiency, complements physical activity by supporting muscle health and vitality—domains that are frequently compromised in aging PWH.³¹ Recent international consensus on the management of sarcopenia recommends multimodal interventions combining resistance exercise with nutritional supplementation, representing an advancement toward proactive muscle health promotion.³¹ Consistent with this approach, higher levels of daily physical activity and better dietary quality have been associated with reduced HIV symptom burden over time, whereas greater sedentary time has been linked to worsening symptoms. These findings underscore the importance of promoting regular physical activity and healthier dietary patterns among PWH as practical strategies to reduce symptom burden and support intrinsic capacity.

Initiatives in HIV care settings demonstrate that collaborative, team-based approaches can successfully incorporate exercise counseling, nutrition support, and referrals to community-based resources, improving care coordination for older PWH with complex needs.^11,32 Psychosocial interventions (including mental health support, stigma reduction, and strategies to reduce social isolation) are increasingly recognized as essential components of nondrug approaches to frailty prevention, given their influence on engagement, adherence, and overall intrinsic capacity. These findings support a shift toward multidimensional, geriatric-informed, nonpharmacologic interventions that address the multifactorial drivers of frailty and sarcopenia in older PWH, thereby preserving function, resilience, and quality of life across the aging trajectory.

Drug Interventions

Among emerging pharmacologic strategies relevant to frailty, sarcopenia, and intrinsic capacity in older PWH, several antiinflammatory, metabolic, and cardiometabolic therapies have shown potential to influence aging trajectories. Recent findings from the ACTG (Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections) A5383 (Randomized, Controlled Trial to Evaluate the Antiinflammatory Efficacy of Letermovir [Prevymis] in Adults with Human Immunodeficiency Virus [HIV]-1 and Asymptomatic Cytomegalovirus [CMV] Who Are on Suppressive ART and Its Effect on Chronic Inflammation, HIV Persistence, and OtherClinical Outcomes [ELICIT]) clinical trial suggest that letermovir, an antiviral targeting cytomegalovirus (CMV), may reduce markers of systemic inflammation, improve CD4+/CD8+ ratios, and support physical function among PWH on suppressive ART.³³ These effects are likely mediated through the suppression of CMV replication, a known contributor to persistent immune activation. Early results further suggest a potential role for CMV-targeted therapy in mitigating chronic age-related conditions through immune aging pathways, which may help preserve domains of intrinsic capacity.

Semaglutide, a glucagon-like protein-1 receptor agonist, may have multidimensional benefits for aging PWH. In the SLIM LIVER (Study of Semaglutide for Non-Alcoholic Fatty Liver Disease [NAFLD], a Metabolic Syndrome With Insulin Resistance, Increased Hepatic Lipids, and Increased Cardiovascular Disease Risk) study, PWH receiving 24 weeks of semaglutide 1 mg had improvements in gait speed despite losses of muscle area;³⁴ in another study of the same semaglutide dose by Eckart and colleagues,³⁵ PWH also experienced loss in muscle mass, but had improvements in some cognitive function domains.³⁶ In SLIM LIVER, changes in DunedinPACE (a DNA-methylation marker of pace of aging) and methylation-derived telomere length paralleled improvements in liver fat and gait speed, and the Eckart study similary found broad deceleration across DunedinPace, and the epigenetic clocks GrimAge and PhenoAge³⁷ and multiomic aging measures.³⁸ The long-term effects of this class of treatments, however, remains to be established and needs more investigation, particularly among older adults.³⁹

Statins are widely used for cardiovascular disease risk reduction, and studies on these drugs contribute to our understanding of unique processes that may underlie aging in PWH. The REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) and its ancillary studies show that pitavastatin does not enhance physical function, but crucially does not impair physical function, with gait speed, chair-rise performance, grip strength, and neurocognitive function remaining stable overa long-term follow-up period.^39,40 Frailty emerged as a powerful predictor of car-diovascular disease risk in REPRIEVE, underscoring the importance of integrating frailty assessment into cardiometabolic management.⁴¹ These findings are particularly relevant given that PWH experience earlier impairments in physical function and a more rapid development of frailty than the general population. Moreover, epigenetic substudy data suggested that although mortality-linked epigenetic age remains unchanged, pitavastatin may help prevent increases in the biologic pace of aging.⁴² In parallel, emerging trials are evaluating agents such as tesamorelin, a growth hormone-releasing hormone analogue approved for HIV-associated abdominal adiposity, to determine whether pharmacologic approaches combined with exercise can improve muscle health, physical function, and quality of life in aging PWH.⁴³

Conclusion

Framing aging with HIV through the lens of intrinsic capacity provides a promising pathway to shift HIV care from disease management toward preservation of functional ability and healthy aging. Growing evidence demonstrates that targeted nondrug, metabolic, and antiinflammatory interventions can help reduce frailty and sarcopenia, and support key domains of intrinsic capacity in older PWH. Integrating this framework into HIV care may improve risk stratification and guide interventions to preserve physical function and quality of life across diverse clinical and social contexts. Continued progress will require incorporating geriatric principles into HIV care, advancing research to refine emerging therapies, and addressing the structural determinants that influence aging trajectories among PWH.