A.K. Nelson1,5, G. Fiskum2, C. Renn3, S. Zhu4, S. Kottilil5, N.J. Klinedinst4
1. University of Maryland School of Nursing, Baltimore, USA; 2. Department of Anesthesiology, University of Maryland, School of Medicine, Baltimore, USA; 3. Pain & Translational Symptom Science, University of Maryland School of Nursing, Baltimore, USA; 4. Department of Organizational Systems and Adult Health, University of Maryland School of Nursing, Baltimore, USA; 5. Institute of Human Virology, University of Maryland, School of Medicine, Baltimore, USA
Corresponding Author: Amy K. Nelson, MS, RN, PhD, 725 W. Lombard Street N143, Baltimore MD 21201, firstname.lastname@example.org, 410-706-0100 fax 410-706-3243
J Frailty Aging 2021;in press
Published online November 19, 2021, http://dx.doi.org/10.14283/jfa.2021.44
People over age 50 living with HIV experience frailty including functional declines and illnesses usually attributed to aging, more frequently and ten years earlier than people without HIV. As the number of people living with HIV over age 50 is expected to triple by the year 2040, those experiencing early frailty will continue to grow. This review synthesizes the known correlates and contributors to musculoskeletal frailty in people living with HIV. A conceptual model of musculoskeletal frailty in HIV that outlines chronic inflammation, altered energy metabolism, immune activation, and endocrine alterations as mechanisms associated with frailty development is presented. Additionally, the potential ability of aerobic exercise to modify the risk of frailty is highlighted as an important intervention.
Key words: Mitochondria, inflammation, immune activation, endocrine alterations, aerobic exercise.
Globally, more than 70% of people living with HIV (PLWH) will be at least aged 50 by 2030 (1). The lifespan for PLWH approaches that of the general population with current antiretroviral therapy (2). Yet physical frailty, defined as an increased vulnerability to stressors, produced by a lack of reserve capacity across multiple physiologic systems (3), places these extended years from middle-age to end-of-life at risk, impacting health, independent function and quality of life. Up to 28% of PLWH over age 50 will experience physical frailty (4). It occurs more frequently and often a decade earlier in PLWH than in age-matched HIV negative counterparts (5–7). Frailty in PLWH is associated with increased rates of hospitalization, longer hospital stays (6, 8), low bone mineral density, falls, more prevalent diabetes and cardiovascular disease (9), worsened cognition (8) and decreased time to death (10).
Frailty is characterized by: 1) weight loss 2) low physical activity 3) self-reported exhaustion 4) slow walking speed and 5) weak grip strength (11). Frailty is identified when three or more of these criteria are present, and pre-frailty, or frailty risk, with two. Frailty was first described in older adults, and the cause is thought to be multifactorial. For example, sarcopenia, increased systemic inflammation, and higher levels of oxidative stress are found in frail elderly adults (12). Less is known about mechanisms driving early frailty in PLWH. While easily understandable within the context of AIDS, when multisystem dysregulation and vulnerabilities occur, it is much less clear why physical frailty would occur in middle-aged adults on antiretrovirals with well-controlled HIV infection.
Frailty has been found to be modifiable with exercise in the elderly (13), yet there are no standard interventions beyond increasing physical activity. For PLWH, exercise interventions are being explored. Yet exercise programs vary by frequency, intensity, length and type producing widely varied results. For younger PLWH who could benefit from early intervention to prevent onset of frailty, even less is known about effective interventions. The purpose of this review is to synthesize the literature and develop a model of contributing mechanisms involved in the development of musculoskeletal frailty in those with HIV while exploring the potential for aerobic activity to as a modifier, decreasing risk of frailty. While frailty can be viewed broadly as poor functioning in physical, cognitive, emotional, sensory or social functioning , this review will focus on the physical aspects of frailty related to musculoskeletal function. The goal is to highlight mechanistic pathways to musculoskeletal frailty and to identify whether exercise interventions may be important for altering these mechanisms producing frailty in middle-aged adults living with HIV. With more than 300,000 adults over 55 living with HIV currently in the United States (15), there is a tremendous unmet need.
This literature review was guided by the model of frailty provided by Piggott, Erlandson and Yarasheski (16). In their work, frailty occurs as a result of factors influencing its development: HIV infection and antiretrovirals, comorbidities, psychosocial and environmental factors and biologic aging. Each can lead to alterations in the mechanistic pathways of altered energy metabolism, inflammation and immune system activation, neuroendocrine function and renin/angiotensin system. While the factors discussed can impact frailty in an aging population, HIV brings additional confounding elements not seen in healthy populations.
Searching the literature in PubMed and CINAHL, search terms were used including “frailty and HIV” with “mitochondria”, “inflammation” and “immune activation”. Articles were reviewed from 2001, when Fried’s physical frailty was defined (11), through 2021 for English articles describing a mechanism for frailty in PLWH. The references of selected articles were also reviewed to find additional works. Earlier articles were reviewed for basic science information. Student thesis or dissertations and book chapters were excluded. Articles were excluded if they did not contribute to the conceptual framework or focused on a specific subpopulation.
Mechanistic Pathways to Frailty in PLWH
Ongoing activation of the immune system by HIV produces chronic levels of inflammation (17). Although antiretroviral agents suppress HIV viral load, only partial resolution of inflammation occurs with cytokines interleukin-10 (IL-10), IL-2 and interferon-gamma (IFN-γ) reducing and becoming comparable to healthy controls (18). However, elevations of tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP), IL-6 and others remain elevated despite long-term viral suppression, suggesting ongoing monocyte/macrophage activation (18, 19). These elevated cytokines are linked to frailty, increased morbidity and mortality in older uninfected adults (20).
Inflammation can also be elicited by injured mitochondria. Free mitochondrial DNA (mtDNA) is recognized by pattern recognition receptors triggering multiple inflammatory pathways. Toll-like receptor 9 (TLR9) recognizes the unmethylated CpG dinucleotides in mtDNA, usually found in bacterial microbes, triggering downstream production of proinflammatory cytokines TNF- α and IL-6 (21). Within intracellular spaces, the inflammasome recognizes mtDNA triggering production of IL-1β and IL-18. Additionally, cytosolic mtDNA can illicit production of type-I interferons via cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathways (21).
Both chronic TNF-α and IL-6 elevations have direct effects on skeletal muscle function. TNF-α has been shown to decrease the force of muscle contractions, much like the impact of excessive reactive oxygen species (ROS) (22). Sustained IL-6 elevations of just two weeks in mouse models have been found to induce muscle fatigue and decrease the content of mitochondrial complexes of the electron transport chain required for oxidative phosphorylation (23). IL-6 elevations can also affect hematopoiesis, which may impact fatigue (24). Decreased contraction force and fatigue from inflammation can easily be seen to impact frailty. Mouse models with decreased anti-inflammatory cytokines with IL-10 knockouts develop weakness, inflammation, increased ROS and are used as models of human frailty (25).
Altered Energy Metabolism
Mitochondria are damaged by the HIV virus, reducing membrane potential, decreasing the size and number of mitochondria and increasing apoptosis (26–28). Damaged mitochondria result in excessive ROS production (29) and decrease energy metabolism as membrane potential is required to drive adenosine triphosphate (ATP) production. Increased ROS can decrease muscle contraction force (30), cause mtDNA loss leading to type II muscle loss (31) and in turn promote inflammatory responses associated with frailty (32).
All of these effects make oxidative phosphorylation, generally the most efficient process for ATP production, inefficient. Dysregulation of the oxidative phosphorylation energy pathway can impact gait speed (33, 34), muscle weakness (25, 35), activity levels (36), fatigue (37) and potentially lead to changes in weight (38). These are all measures of a physical frailty phenotype. Genomic mouse models producing excessive ROS similar to mitochondrial dysfunction display frailty effects. The Copper/Zinc Superoxide Dismutase Knockout (Sod1KO) that lack the enzyme superoxide dismutase in the cytosol to catalyze superoxides to hydrogen peroxide display four of the five frailty criteria (39).
Microbial translocation occurs when the epithelial lining of the digestive tract is damaged from HIV infection. As the lining of the digestive tract becomes more permeable and immune surveillance decreases, microbes and bacterial metabolites can more easily cross into the blood stream, and be detected by pattern recognition receptors, activating the innate immune system and leading to further dysregulation and production of pro-inflammatory cytokines (40). An abnormal gut microbiome can also result in release of bacterial toxins that adversely affect neuromuscular activities (41). In addition, HIV infected individuals have selective depletion of gut-associated mucosal tissue CD4+ T cells and IL-17 producing T cells. As CD4+ T cells are required for effective immunoglobin (Ig) isotype switching, this results in excessive IgM secretions promoting inflammation, while IgG and IgA responses are decreased allowing further enhancement of microbial translocation (42). Decreased IL-17 production impacts immune protection of the gut epithelium, furthering gut dysbiosis (43).
Despite effective therapy, the CD4+ and CD8+ cells of PLWH display increased markers of immune activation (HLA-DR, CD38) and proliferation (Ki67) (44). Studies identify factors such as loss of CD28 expression (45, 46), increased neopterin, a marker of macrophage activation by interferon-gamma (IFN-γ) (45), monocyte expression of CD16+, increased CD8:CD4 ratios (47), higher expression of CCR5+ in CD8 cells (47) and increased CD38+ B cells (46). Increased monocyte/macrophage activation (sCD163) has also been shown in HIV to be associated with arterial inflammation (48), with noncalcified coronary plaques (49), and insulin resistance (50).
However, identifying the major mechanisms linking immune activation in HIV with frailty will require completion of longitudinal studies, especially as PLWH have different immune activation patterns and more baseline activation than those non-infected, regardless of frailty. For this reason, it is not enough to simply compare levels of immune activation between PLWH and uninfected controls. Immune activation in HIV leads to cytokine production, which in turn contributes to inflammation. Additionally, as immune cells become activated they drive toward glycolysis (51). This shift reduces overall energy production as oxidative phosphorylation is nineteen times more efficient at producing ATP (52) though glycolysis allows activated cells to utilize energy up to one hundred times faster (53). Generally, the adaptive immune system must fluctuate between these processes from naïve, to activated, then to apoptosis or memory cells. The innate immune system relies more heavily on glycolysis. Chronic immune activation, as is seen in HIV can then be seen to disrupt the delicate balance and unfavorably alter overall energy metabolism.
PLWH have been noted to experience a number of endocrine alterations, some directly affected by HIV itself, others from changes in body composition as a result of HIV. It is well known that testosterone is often decreased, with approximately 20% of men living with HIV experiencing secondary hypogonadism (54). Along with expected symptoms, hypogonadism leads to decreased muscular strength, energy levels, bone mineral density and can lead to normocytic anemia, further accentuating frailty symptoms (54). Growth hormone levels are affected by changes in body composition (55) and correlate inversely with central adiposity commonly seen in PLWH. Lipodystrophy found in PLWH has been associated with both low growth hormone and Insulin-like growth factor 1 (IGF-1), which are important regulators of both sarcopenia and decreased bone mineral density (54), and IGF-1 is being utilized as a biomarker for frailty (56).
Risk Factors Related to Musculoskeletal Frailty
The factors below are all associated with risk of frailty and relate to the alterations in inflammation, energy metabolism, immune activation and endocrine pathways to musculoskeletal frailty.
Antiretroviral therapy (ART) can induce mitochondrial toxicity (57, 58). Recently it has been found that while ART can help to restore immune system energy metabolism, CD4+ T cells continue to have decreased respiration. This was notably worse when integrase strand transfer inhibitors (INSTI) were used, with ongoing CD4+ cell impairment of cellular respiration and function (59) impacting ATP production.
The long-used class of nucleoside-analogue reverse transcriptase inhibitors (NRTI’s) inhibit mitochondrial DNA (mtDNA) polymerase-γ involved in mtDNA replication and repair . This mitochondrial damage can lead to increased ROS and decreased ATP production (61). Additionally, ART has been associated with glucose metabolism disorders. A study of adult PLWH on ART compared to treatment naïve PLWH and uninfected controls found rates of glucose metabolism disorders six-times higher in those on ART than uninfected controls who had similar rates to PLWH naïve to therapy (62).
Bone density has been shown to decrease by 3-6% once ART commences, particularly with nucleoside analogues and protease inhibitors (63). Direct effects of HIV proteins Tag and Nef also lead to decreased bone formation by impacting stem cell precursors for osteoblasts (55). The delicate balance of bone growth and resorption is altered, favoring bone resorption for PLWH (55). Additionally, protease boosted ART regimens have been implicated in bone fracture (54).
People with HIV also live with comorbid conditions that impact frailty. For example, 2% of PLWH have chronic hepatitis B , 6.7% have active hepatitis C (65), and almost all have cytomegalovirus (66). Each of these conditions are known to increase immune activation (67). Diabetes and insulin resistance are proinflammatory and reduce mitochondrial energy production (68) and are more common in PLWH than uninfected adults (69). Moreover, chronic kidney disease, peripheral arterial disease, rheumatoid arthritis, cardiovascular disease, pulmonary disease and anemia also increase inflammation and immune activation (70). Unfortunately, these comorbidities are more prevalent in PLWH and may play a role in the early development of frailty.
Pain has been associated with frailty (71) in PLWH and may be an important covariate. It is estimated that between 25% to 90% of PLWH also have chronic pain, mainly in the joints, head, legs and back (72). Chronic pain often leads to decreases in physical function as people adopt a sedentary lifestyle to cope with the pain. It is likely that as pain decreases physical function, frailty risks increase, particularly the risks of sarcopenia and muscle weakness (73). Recent work has identified the role of mitochondrial damage and endoplasmic reticulum calcium dysregulation producing nociceptor sensitization and chronic pain (74). The bidirectional interactions between inflammation and the immune system in pain sensitivity also explain crossover with frailty risk. Cytokines IL-1ß, IL-6, TNF-α and others can act directly on nociceptors to produce pain, and immune cells such as macrophages and neutrophils can be recruited to sites of inflammation, producing more of these cytokines (75).
Finally, polypharmacy has been strongly associated with development of frailty, though causality is not yet well defined (76). With varied definitions of polypharmacy ranging from four to more than ten daily medications, and mainly cross-sectional study designs, more research is needed to explore the positive correlation of polypharmacy with frailty in PLWH.
Psychosocial and Environmental Factors
Cognitive and mental health may have overlapping development pathways with frailty in terms of neuroinflammation, nutritional status, and oxidative stress (77). Depression appears to have a bidirectional relationship with frailty, with approximately 40% of those with depression experiencing frailty, and the same proportion of those with frailty experiencing depression in a recent meta-analysis (78). Additionally, stressors such as low socioeconomic status and less than twelve years of education have been shown to increase stress and the relative odds of frailty by 2.7 and 3.5 respectively in uninfected older adults (79). Smoking and substance abuse are also contributors in the development of frailty increasing inflammation and oxidative stress (80). Moderate to severe alcohol ingestion has been shown to increase immune activation and inflammation (81), thus contributing to frailty. PLWH have been found to experience increased rates of depression, smoking, substance abuse, depression and socioeconomic stressors (82–85) increasing frailty risks.
Nutrition, or more specifically the lack of proteins and essential nutrients can be associated with weight loss, muscle loss, and frailty. Sufficient intake of protein and micronutrients are required to avoid anemia and to preserve muscle mass (77, 86). However, if excessive calories are consumed, or activity is insufficient, central adiposity can occur which is also related to frailty (87). Adipose tissue releases pro-inflammatory adipokines such as TNF-α, IL-6 and CRP causing low grade chronic inflammation and risk of numerous diseases (88). Saturated fatty acids in foods also lead to increases in pro-inflammatory cytokines (86). These pro-inflammatory molecules are also associated with frailty, both in healthy older adults and in PLWH of younger ages (67, 89).
Biologic aging is significant in the role of HIV for frailty risk. Part of normal aging is the loss of telomeres with cell proliferation. A study of PLWH aged 45 and above found shorter telomeres on immune cells in PLWH, despite long-term viral suppression, than in uninfected subjects. This was associated with greater CD4+ activation and monocyte activation markers sCD14 and sCD163 (90). This relationship with immune activation may be important, though telomere length has had varying associations with frailty (91). Age by measure of DNA methylation has also been able to show increased epigenetic age by approximately 14 years in PLWH aged 20 to 56 in brain and blood tissue compared to controls (92, 93). Another recent study of people coinfected with HIV and hepatitis C found that the HIV is driving epigenetic aging not seen in people with hepatitis C alone (94). These emerging fields may help to verify mechanisms of early frailty as more research is completed.
Aerobic Activity as a Potential Moderator of Musculoskeletal Frailty in PLWH
The Health, Aging, and Body Composition study followed nearly 3000 healthy adult subjects 70 to 79 years old over five years assessing frailty and physical activity. It found that those who exercised were less likely to develop frailty (OR=1.45), and three-times less likely to progress from moderate to severe frailty (95), demonstrating the importance of physical activity to modify frailty risks. Less is known about the ability of aerobic exercise to decrease immune activation in PLWH, with mixed results to date (96, 97). However, aerobic activity is an intervention that is known to influence the physiologic mechanisms of frailty in HIV.
Exercise and Chronic Inflammation
Multiple studies have shown that exercise can reduce inflammatory markers such as IL-6, TNF-α, and CRP (96, 98, 99). Healthy but inactive older adults have been found to have a greater percentage (13.3 +/- 2.8% vs. 7.5 +/- 2.1%) of inflammatory monocytes (CD14+CD16+) than physically active matched controls (100). When these physically active and inactive adults aged 65 to 80 were assessed after the inactive group completed twelve weeks of walking and resistance exercise, the inflammatory monocyte percentages became comparable (PA: 6.47 +/- 0.8% vs. PI: 4.75 +/- 0.5%)  and was found to significantly correlate with TNF-α but not BMI. While this study showed no impact on CRP, other large cohorts have found an impact on CRP including the British Regional Heart study (101), the Third National Health and Nutrition Examination Survey (NHANESIII) (102), the Cardiovascular Health study (CHS) , and the Health ABC study (104). In a study of independent seniors, those most active were found to have the lowest levels of IL-6 and TNF-α (105). Additionally, a meta-analysis of exercise interventions in PLWH with mean age of 42 showed reduced IL-6 by 2.4 ng/dl (95% CI: -2.6 to -2.1, p< 0.001) in the adults who exercised compared to those who did not (104). Yet another meta-analysis of exercise interventions of at least four-week duration in PLWH showed no benefit in reducing inflammatory markers (106). A meta-analysis conducted by Chaparro (2018) included just two studies both with control groups that did not exercise. The interventions lasted six to twelve weeks, and both studies noted favorable changes in body composition. The Ibeneme analysis (2019), included both randomized controlled trials and case control studies, but had no specifications on type or intensity of the exercise intervention.
Exercise and Altered Energy Metabolism
Regular aerobic activity has anti-inflammatory effects and improves systemic mitochondrial energy production in uninfected adults (30, 88, 108). A program of twelve weeks of aerobic exercise in a small number of older adults showed increased mitochondrial content of 50% with significant increases in both mtDNA copy numbers and electron transport chain activity (109). In elderly adults, an intervention of 16 weeks aerobic exercise showed increased mitochondrial biogenesis and upregulation of the genes which regulate the process (110).
It has also been shown that energy metabolism efficiency correlates with activity levels, and not just chronologic age. In younger PLWH, one study testing twelve weeks of aerobic exercise in seven subjects, ages 36 to 58, reported a 5.65-fold increase in mitochondrial spare respiratory capacity in peripheral blood mononuclear cells (111). Spare respiratory capacity represents the difference between the basal respiratory capacity and maximal respiratory capacity of mitochondria, the ability to respond to increased cellular energy requirements. This indicates that exercise is useful for increasing cellular spare respiratory capacity. Additional studies are needed to confirm these potentially important findings.
Exercise and Immune Activation
While a single episode of intense exercise was once considered immunosuppressive, evidence now reported from athletes dispels the notion that this may result in more frequent infections. Additionally, the transient increase and decline of PBMCs post-exertion once thought to signify immunosuppression is now regarded as a form of enhanced immune surveillance as cells are redistributed to peripheral tissues after exercise (112). It is important to focus studies on the immune compartments being affected, along with their function outside of the bloodstream to gain a more complete picture of the effects of acute exercise. For example, response to vaccine can be improved with a single episode of aerobic activity (113). Exercise in mice has been shown to increase microbial diversity in the gut microbiome, potentially impacting immune activation (114).
Comparisons of study findings remain challenging for longer-term aerobic exercise interventions. Impact on immune activation vary widely by study. However, a small study was conducted in sedentary PLWH with a mean age of 48, testing 60 minutes of brisk walking with or without strength training three times weekly over twelve weeks. They found reduced CD8+/CD38+/HLA-DR+ activated T-cells in both groups, along with improved inflammatory markers only in the walking group (96). This suggests that sedentary PLWH may provide an initial population in which to test short-term aerobic exercise interventions.
Exercise and Endocrine Alterations
Chronic aerobic exercise is known to have potential impact on BMI and affects insulin sensitivity which can be altered by innate immune system activity and ongoing inflammation (115). Insulin plays a role in T cell activation growth and function due to the presence of an insulin receptor on activated T cells, producing an anti-inflammatory type response (116). Additionally, even acute exercise has been shown to improve testosterone levels in PLWH (117).
Certainly, if excess visceral fat is lost as a result of aerobic activity, there are benefits. Adipocytes release inflammatory adipokines such as IL-1, IL-6, IFN-α and TNF-α and also promote trafficking of both monocytes and lymphocytes into the adipose tissue (52). These deleterious effects can be compounded with HIV triggered immune activation, and lead to both inflammation and muscle loss (118). Not all clinical trial exercise interventions produce changes in total body fat or BMI within the short time frames of study. However, this assists in understanding if intervention mechanisms correlate with change in BMI.
Middle-aged PLWH are at serious risk of developing frailty. Based on this review, a conceptual model of frailty in HIV has been developed that builds on the work by Piggott, Erlandson & Yarasheski (2016). The low-level chronic inflammation, mitochondrial dysfunction, immune system activation and endocrine dysregulation act as pathways for frailty development (Figure 2). These changes impact energy levels and muscle strength associated with frailty criteria. Multiple risk factors act through these pathways such as ART drug class, other inflammatory conditions, pain, nutritional deficits or central adiposity, coinfections and even the HIV virus itself.
Unfortunately, there are no standard interventions for those at risk. While multiple activity interventions are being investigated in PLWH, fewer are targeting middle-aged adults who might see greatest benefit from aerobic activity. As exercise intervention study design is highly variable, and as the populations targeted also vary, it becomes important to understand the mechanisms being impacted. We propose that interventional studies collect data on inflammatory markers, mitochondrial energy production and immune activation in order to better understand the mechanistic impact of exercise on musculoskeletal frailty in HIV. Aerobic exercise during mid-life will likely be important to prevent or delay early frailty and lessen the effects of mitochondrial dysfunction, inflammation, immune dysfunction and endocrine alterations in this at-risk population.
Conflicts of Interest: None.
Ethical standards: None.
1. Smit M, Brinkman K, Geerlings S, et al. Future challenges for clinical care of an ageing population infected with HIV: A modelling study. Lancet Infect Dis 2015;15:810–818 https://doi.org/10.1016/S1473-3099(15)00056-0
2. Trickey A, May MT, Vehreschild JJ, et al. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV 2017;4:e349–e356 https://doi.org/ 10.1016/S2352-3018(17)30066-8
3. Walston J, Robinson TN, Zieman S, et al. Integrating Frailty Research into the Medical Specialties—Report from a U13 Conference. J Am Geriatr Soc 2017;65:2134–2139 https://doi.org/10.1111/jgs.14902
4. Levett TJ, Cresswell F V., Malik MA, Fisher M, Wright J. Systematic Review of Prevalence and Predictors of Frailty in Individuals with Human Immunodeficiency Virus. J Am Geriatr Soc 2016;64:1006–1014 https://doi.org/10.1111/jgs.14101
5. Desquilbet L, Jacobson LP, Fried LP, et al. HIV-1 Infection Is Associated With an Earlier Occurrence of a Phenotype Related to Frailty. J Gerontol A Biol Sci Med Sci 2011;62:1279–1286 https://doi.org/10.1093/gerona/62.11.1279
6. Önen NF, Agbebi A, Shacham E, Stamm KE, Önen AR, Overton ET. Frailty among HIV-infected persons in an urban outpatient care setting. J Infect 2009;59:346–352 https://doi.org/10.1016/j.jinf.2009.08.008
7. Willig AL, Overton ET, Saag MS. The Silent Epidemic – Frailty and Aging with HIV. Total Patient Care in HIV & HCV 2017;1:6–17
8. Wallace LMK, Ferrara M, Brothers TD, et al. Lower Frailty Is Associated with Successful Cognitive Aging among Older Adults with HIV. AIDS Res Hum Retroviruses 2017;33:157–163 https://doi.org/10.1089/aid.2016.0189
9. Kelly SG, Wu K, Tassiopoulos K, Erlandson KM, Koletar SL, Palella FJ. Frailty is an independent risk factor for mortality, cardiovascular disease, bone disease and diabetes among aging adults with HIV. Clin Infect Dis 2019;69:1370–1376 https://doi.org/10.1093/cid/ciy1101
10. Piggott DA, Muzaale AD, Mehta SH, et al. Frailty, HIV Infection, and Mortality in an Aging Cohort of Injection Drug Users. PLoS One 2013;8 https://doi.org/10.1371/journal.pone.0054910
11. Fried LP. ., Tangen CM., Walston J., et al. Frailty in older adults: evidence for a phenotype. J Gerontol 2001;56A:M146-56 https://doi.org/10.1093/gerona/56.3.m146
12. Ershler WB. A gripping reality : oxidative stress , inflammation , and the pathway to frailty. J Appl Physiol 2007;3–5 https://doi.org/10.1152/japplphysiol.00375.2007
13. Cesari M, Vellas B, Hsu FC, et al. A physical activity intervention to treat the frailty syndrome in older persons – Results from the LIFE-P study. J Gerontol A Biol Sci Med Sci 2015;70:216–222 https://doi.org/10.1093/gerona/glu099
14. Guralnik JM, Simonsick EM. Physical disability in older Americans. Journals Gerontol 1993;48:3–10 https://doi.org/10.1093/geronj/48.special_issue.3
15. Linley L, Johnson AS, Song R, et al. Estimated HIV incidence and prevalence in the United States, 2010–2016. HIV Surveill Suppl Rep 2019;24
16. Piggott, Damani A.; Erlandson, Kristine M.; Yarasheski KE. Frailty in HIV: Epidemiology, Biology, Measurement, Interventions, and Research Needs. Curr HIV/ AIDS Rep 2016;13:340–348 https://doi.org/10.1007/s11904-016-0334-8
17. Nasi M, De Biasi S, Gibellini L, et al. Ageing and inflammation in patients with HIV infection. Clin Exp Immunol 2017;187:44–52 https://doi.org/10.1111/cei.12814
18. Wada NI, Jacobson LP, Margolick JB, et al. The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation. AIDS 2015 https://doi.org/10.1097/QAD.0000000000000545
19. Regidor DL, Detels R, Bren EC, et al. Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation. AIDS 2011;25:303–314 https://doi.org/10.1038/jid.2014.371
20. Leng SX, Margolick JB. Understanding Frailty, Aging and Inflammation in HIV Infection. Curr HIV/AIDS Rep 2015;12:25–32 https://doi.org/10.1007/s11904-014-0247-3
21. Grazioli S, Pugin J. Mitochondrial damage-associated molecular patterns: From inflammatory signaling to human diseases. Front Immunol 2018;9:1–17 https://doi.org/10.3389/fimmu.2018.00832
22. Reid MB, Lännergren J, Westerblad H. Respiratory and Limb Muscle Weakness Induced by Tumor Necrosis Factor- α. Am J Respir Crit Care Med 2002;166:479–484
23. VanderVeen BN, Fix DK, Montalvo RN, et al. The regulation of skeletal muscle fatigability and mitochondrial function by chronically elevated interleukin-6. Exp Physiol 2019;104:385–397
24. Leng S, Chaves P, Koenig K, Walston J. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: A pilot study. J Am Geriatr Soc 2002;50:1268–1271 https://doi.org/10.1046/j.1532-5415.2002.50315.x
25. Akki A, Yang H, Gupta A, et al. Skeletal muscle ATP kinetics are impaired in frail mice. Age (Omaha) 2014;36:21–30 https://doi.org/10.1007/s11357-013-9540-0
26. Rodríguez-Mora S, Mateos E, Moran M, et al. Intracellular expression of Tat alters mitochondrial functions in T cells: A potential mechanism to understand mitochondrial damage during HIV-1 replication. Retrovirology 2015;12:1–24 https://doi.org/10.1186/s12977-015-0203-3
27. Rozzi SJ, Avdoshina V, Fields JA, Mocchetti I. Human immunodeficiency virus Tat impairs mitochondrial fission in neurons. Cell Death Discov 2018;4:8 https://doi.org/10.1038/s41420-017-0013-6
28. Villeneuve LM, Purnell PR, Stauch KL, Callen SE, Buch SJ, Fox HS. HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution. J Neurovirol 2016;22:564–574 https://doi.org/10.1007/s13365-016-0424-9
29. Hood DA, Memme JM, Oliveira AN, Triolo M. Maintenance of Skeletal Muscle Mitochondria in Health, Exercise, and Aging. Annu Rev Physiol 2019;81:19–41 https://doi.org/10.1146/annurev-physiol-020518-114310
30. Hood DA. Plasticity in Skeletal, Cardiac, and Smooth Muscle Invited Review: Contractile activity-induced mitochondrial biogenesis in smooth muscle. J Appl Physiol 2001;90:1137–1157 https://doi.org/https://doi.org/10.1152/jappl.2001.90.3.1137
31. Wanagat J, Cao Z, Pathare P, Aiken JM. Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia. FASEB J 2001;15:322– 332 https://doi.org/10.1096/fj.00-0320com
32. Inglés M, Gambini J, Carnicero JA, et al. Oxidative stress is related to frailty, not to age or sex, in a geriatric population: Lipid and protein oxidation as biomarkers of frailty. J Am Geriatr Soc 2014;62:1324–1328 https://doi.org/10.1111/jgs.12876
33. Sun J, Brown TT, Samuels DC, et al. The Role of Mitochondrial DNA Variation in Age-Related Decline in Gait Speed among Older Men Living with Human Immunodeficiency Virus. Clin Infect Dis 2018;67:778–784 https://doi.org/10.1093/cid/ciy151
34. Tyrrell DJ, Bharadwaj MS, Van Horn CG, Kritchevsky SB, Nicklas BJ, Molina AJA. Respirometric Profiling of Muscle Mitochondria and Blood Cells Are Associated With Differences in Gait Speed Among Community-Dwelling Older Adults. Journals Gerontol – Ser A Biol Sci Med Sci 2015;70:1394–1399 https://doi.org/10.1093/gerona/glu096
35. Peterson CM, Johannsen DL, Ravussin E. Skeletal Muscle Mitochondria and Aging: A Review. J Aging Res 2012;2012:1–20 https://doi.org/10.1155/2012/194821
36. Toledo FGS, Dubé JJ, Goodpaster BH, Stefanovic-Racic M, Coen PM, DeLany JP. Mitochondrial Respiration is Associated with Lower Energy Expenditure and Lower Aerobic Capacity in African American Women. Obesity 2018;26:903–909 https://doi.org/10.1002/oby.22163
37. Lavorato M, Loro E, Debattisti V, Khurana TS, Franzini-Armstrong C. Elongated mitochondrial constrictions and fission in muscle fatigue. J Cell Sci 2018;131:1–8 https://doi.org/10.1242/jcs.221028
38. Tyrrell DJ, Bharadwaj MS, Van Horn CG, Marsh AP, Nicklas BJ, Molina AJA.Blood-cell bioenergetics are associated with physical function and inflammation in overweight/obese older adults. Exp Gerontol 2015;70:84–91 https://doi.org/10.1016/j.exger.2015.07.015
39. Deepa SS, Bhaskaran S, Espinoza S, et al. A new mouse model of frailty: the Cu/Zn superoxide dismutase knockout mouse. GeroScience 2017;39:187–198 https://doi.org/10.1007/s11357-017-9975-9
40. Piggott DA, Tuddenham S. The gut microbiome and frailty. Transl. Res. . 2020. Mosby Inc., 221: 23–43 https://doi.org/10.1016/j.trsl.2020.03.012
41. Dempsey JL, Little M, Cui JY. Gut microbiome: An intermediary to neurotoxicity. Neurotoxicology 2019;75:41–69 https://doi.org/10.1016/j.neuro.2019.08.005
42. Hel Z, Xu J, Denning WL, et al. Dysregulation of Systemic and Mucosal Humoral Responses to Microbial and Food Antigens as a Factor Contributing to Microbial Translocation and Chronic Inflammation in HIV-1 Infection. PLoS Pathog 2017;13:1–20 https://doi.org/10.1371/journal.ppat.1006087
43. Tincati C, Douek DC, Marchetti G. Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection. AIDS Res Ther 2016;13:19 https://doi.org/10.1186/s12981-016-0103-1
44. Paiardini M, Müller-Trutwin M. HIV-associated chronic immune activation. Immunol Rev 2013;254:78–101 https://doi.org/10.1111/imr.12079
45. Li H, Manwani B, Leng SX. Frailty, inflammation, and immunity. Aging Dis 2011;2:466–473
46. Lu Y, Tze C, Tan Y, et al. Inflammatory and immune markers associated with physical frailty syndrome : findings from Singapore longitudinal aging studies. Oncotarget 2016;7:28783–95 https://doi.org/https://doi.org/10.18632/oncotarget.8939
47. De Fanis U, Wang GC, Fedarko NS, Walston JD, Casolaro V, Leng SX. T-lymphocytes expressing CC chemokine receptor-5 are increased in frail older adults. J Am Geriatr Soc 2008;56:904–908 https://doi.org/10.1111/j.1532-5415.2008.01673.x
48. Fitch K V., DeFilippi C, Christenson R, et al. Subclinical myocyte injury, fibrosis and strain in relationship to coronary plaque in asymptomatic HIV-infected individuals. AIDS 2016;30:2205–2214 https://doi.org/10.1097/QAD.0000000000001186
49. Fitch K V., Srinivasa S, Abbara S, et al. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis 2013;208:1737–1746 https://doi.org/10.1093/infdis/jit508
50. Shikuma CM, Chow DC, Gangcuangco LMA, et al. Monocytes expand with immune dysregulation and is associated with insulin resistance in older individuals with chronic HIV. PLoS One 2014;9:1–9 https://doi.org/10.1371/journal.pone.0090330
51. Fenwick C, Joo V, Jacquier P, et al. T-cell exhaustion in HIV infection. Immunol. Rev. 2019; 292:149–63 doi: 10.1111/imr.12823 https://doi.org/10.1111/imr.12823
52. Delmastro-Greenwood MM, Piganelli JD. Changing the energy of an immune response. Am J Clin Exp Immunol 2013;2:30–54
53. Pfeiffer T, Schuster S, Bonhoeffer S. Cooperation and competition in the evolution of ATP-producing pathways Science 2001; 292:504-507 https://doi.org/10.1126/science.293.5534.1436
54. Tamez-Rivera O, Martinez-Ayala P, Navarrete-Reyes AP, Amieva H, Avila-Funes JA. Molecular crossroads of frailty and HIV. J Frailty Aging 2014;3:89–96 https://doi.org/10.14283/jfa.2014.7
55. Zaid D, Greenman Y. Human immunodeficiency virus infection and the endocrine system. Endocrinol Metab 2019;34:95–105 https://doi.org/10.3803/EnM.2019.34.2.95
56. Chew J, Tay L, Lim JP, et al. Serum Myostatin and IGF-1 as Gender-Specific Biomarkers of Frailty and Low Muscle Mass in Community-Dwelling Older Adults. J Nutr Heal Aging 2019;23:979–986 https://doi.org/10.1007/s12603-019-1255-1
57. Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 1999;354:1112– 1115 https://doi.org/10.1016/S0140-6736(99)06102-4
58. Roge, B., Calbet JAL, Mùller K et al. Skeletal muscle mitochondrial function and exercise capacity in HIV-infected patients with lipodystrophy and elevated p-lactate levels. AIDS 2002, 16:973-982. https://doi.org/10.1097/00002030-200205030-00003
59. Korencak M, Byrne M, Richter E, et al. Effect of HIV infection and antiretroviral therapy on immune cellular functions. JCI Insight 2019;4 https://doi.org/10.1172/jci.insight.126675
60. Smith RL, Tan JME, Jonker MJ, et al. Beyond the polymerase-γ theory: Production of ROS as a mode of NRTI-induced mitochondrial toxicity. PLoS One 2017;12:1–23 https://doi.org/10.1371/journal.pone.0187424
61. Kohler JJ, Lewis W. A Brief Overviewof Mechanisms of Mitochondrial Toxicity From NRTIs. Environ Mol Mutagen 2007;48:166–172 https://doi.org/10.1002/em
62. Maganga E, Smart LR, Kalluvya S, et al. Glucose metabolism disorders, HIV and antiretroviral therapy among tanzanian adults. PLoS One 2015;10:1–13 https://doi.org/10.1371/journal.pone.0134410
63. Brown TT, Qaqish RB. Response to Berg et al. “Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: A meta-analytic review” . Aids 2007;21:1830–1831 https://doi.org/10.1097/QAD.0b013e3282703837
64. Marinos G, Tor F, Chokshi S, et al. Induction of T-Helper Cell Response to Hepatitis B Core Antigen in Chronic Hepatitis B: A Major Factor in Activation of the Host Immune Response to the Hepatitis B Virus. Hepatology 1995;22:1040-1049 https://doi.org/10.1016/0270-9139(95)90607-X
65. Gonzalez VD, Falconer K, Blom KG, et al. High Levels of Chronic Immune Activation in the T-Cell Compartments of Patients Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus Type 1 and on Highly Active Antiretroviral Therapy Are Reverted by Alpha Interferon and Ribavirin Treatment. J Virol 2009;83:11407–11411 https://doi.org/10.1128/jvi.01211-09
66. Margolick JB, Bream JH, Nilles TL, et al. Relationship between T-Cell responses to CMV, markers of inflammation, and frailty in HIV-uninfected and HIV-infected men in the multicenter AIDS cohort study. J. Infect. Dis. 2018. Oxford University Press, pp 249–258 https://doi.org/10.1093/infdis/jiy005
67. Cheng W-J, Palmer CS, Landay AL, et al. HIV infection induces age-related changes to monocytes and innate immune activation in young men that persist despite combination antiretroviral therapy. AIDS 2012 https://doi.org/10.1097/qad.0b013e328351f756
68. Takemoto JK, Miller TL, Wang J, et al. Insulin resistance in HIV-infected youth is associated with decreased mitochondrial respiration. AIDS 2017;31:15–23 https://doi.org/10.1097/QAD.0000000000001299
69. Yang HY, Beymer MR, Suen S chuan. Chronic Disease Onset Among People Living with HIV and AIDS in a Large Private Insurance Claims Dataset. Sci Rep 2019;9:1–8 https://doi.org/10.1093/infdis/jiy005
70. Chang SS, Weiss CO, Xue QL, Fried LP. Association between inflammatory-related disease burden and frailty: Results from the Women’s Health and Aging Studies (WHAS) I and II. Arch Gerontol Geriatr 2012;54:9–15 https://doi.org/10.1016/j.archger.2011.05.020
71. Petit N, Enel P, Ravaux I, et al. Frail and pre-frail phenotype is associated with pain in older HIV-infected patients. Medicine (Baltimore) 2018;97 https://doi.org/10.1097/MD.0000000000009852
72. Addis DR, DeBerry JJ, Aggarwal S. Chronic Pain in HIV. Mol. Pain . 2020. SAGE Publications Inc., 16 https://doi.org/10.1177/1744806920927276
73. Merlin JS, Westfall AO, Chamot E, et al. Pain is independently associated with impaired physical function in HIV-infected patients. Pain Med (United States) 2013;14:1985–1993 https://doi.org/10.1111/pme.12255
74. Yousuf MS, Maguire AD, Simmen T, Kerr BJ. Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection. Molecular Pain . 2020. 16:1-20. https://doi.org/10.1177/1744806920946889
75. Pinho-Ribeiro FA, Verri WA, Chiu IM. Nociceptor Sensory Neuron–Immune Interactions in Pain and Inflammation. Trends Immunol 2017;38:5–19 https://doi.org/10.1016/j.it.2016.10.001
76. Gutiérrez-Valencia M, Izquierdo M, Cesari M, Casas-Herrero, Inzitari M, Martínez- Velilla N. The relationship between frailty and polypharmacy in older people: A systematic review. Br. J. Clin. Pharmacol. 2018. Blackwell Publishing Ltd, 84: 1432–1444 https://doi.org/10.1111/bcp.13590
77. Dominguez LJ, Barbagallo M. The relevance of nutrition for the concept of cognitive frailty. Curr. Opin. Clin. Nutr. Metab. Care . 2017. Lippincott Williams and Wilkins, 20: 61–68 https://doi.org/10.1097/MCO.0000000000000337
78. Soysal P, Veronese N, Thompson T, et al. Relationship between depression and frailty in older adults: A systematic review and meta-analysis. Ageing Res Rev 2017;36:78–87 https://doi.org/10.1016/j.arr.2017.03.005
79. Szanton SL, Seplaki CL, Thorpe RJ, Allen JK, Fried LP. Socioeconomic status is associated with frailty: The Women’s Health and Aging Studies. J Epidemiol Community Health 2010;64:63–67 https://doi.org/10.1136/jech.2008.078428
80. Womack JA, Justice AC. The OATH Syndemic: opioids and other substances, aging, alcohol, tobacco, and HIV. Curr Opin HIV AIDS 2020;15:218–225 https://doi.org/10.1097/COH.0000000000000635
81. Monnig MA, Cohen R, Ramratnam B, McAdams M, Tashima K, Monti PM. HIV Infection, HCV Coinfection, and Alcohol Use: Associations with Microbial Translocation and Immune Activation. Alcohol Clin Exp Res 2019;43:1126–1134 https://doi.org/10.1111/acer.14032
82. Ownby RL. Depression care and prevalence in HIV-positive individuals. Neurobehav HIV Med 2010;73 https://doi.org/10.2147/nbhiv.s7296
83. Mdodo R, Frazier EL, Dube SR, et al. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: Cross- sectional surveys. Ann Intern Med 2015;162:335–344 https://doi.org/10.7326/M14-0954
84. Chander G, Himelhoch S, Moore RD. Substance abuse and psychiatric disorders in HIV-positive patients: Epidemiology and impact on antiretroviral therapy. Drugs 2006;66:769–789 https://doi.org/10.2165/00003495-200666060-00004
85. Ikeda MLR, Barcellos NT, Alencastro PR, et al. Alcohol drinking pattern: A comparison between HIV-infected patients and individuals from the general population. PLoS One 2016;11:1–10 https://doi.org/10.1371/journal.pone.0158535
86. Perna S, Alalwan TA, Al-Thawadi S, et al. Evidence-Based role of nutrients and antioxidants for chronic pain management in musculoskeletal frailty and sarcopenia in aging. Geriatr 2020;5:1-12 https://doi.org/10.3390/geriatrics5010016
87. Hawkins KL, Zhang L, Ng DK, et al. Abdominal obesity, sarcopenia, and osteoporosis are associated with frailty in men living with and without HIV. AIDS 2018;32:1257–1266 https://doi.org/10.1097/QAD.0000000000001829
88. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti- inflammatory effects of exercise: Mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 2011;11:607–610 https://doi.org/10.1038/nri3041
89. Van Epps P, Oswald D, Higgins PA, et al. Frailty has a stronger association with inflammation than age in older veterans. Immun Ageing 2016;13:1–9 https://doi.org/10.1186/s12979-016-0082-z
90. Jimenez VC, Wit FWNM, Joerink M, et al. T-Cell Activation Independently Associates with Immune Senescence in HIV-Infected Recipients of Long-term Antiretroviral Treatment. J Infect Dis 2016;214:216–225 https://doi.org/10.1093/infdis/jiw146
91. Araújo Carvalho AC, Tavares Mendes ML, da Silva Reis MC, Santos VS, Tanajura DM, Martins-Filho PRS. Telomere length and frailty in older adults—A systematic review and meta-analysis. Ageing Res. Rev. 2019. Elsevier Ireland Ltd, 54 https://doi.org/10.1016/j.arr.2019.100914
92. Horvath S, Levine AJ. HIV-1 infection accelerates age according to the epigenetic clock. J Infect Dis 2015;212:1563–1573 https://doi.org/10.1093/infdis/jiv277
93. Rickabaugh TM, Baxter RM, Sehl M, et al. Acceleration of age-associated methylation patterns in HIV-1-infected adults. PLoS One 2015;10 https://doi.org/10.1371/journal.pone.0119201
94. Gindin Y, Gaggar A, Lok AS, et al. DNA Methylation and Immune Cell Markers Demonstrate Evidence of Accelerated Aging in Patients with Chronic HBV or HCV, with or without HIV Co-Infection. Clin Infect Diseases 2020 2020 Sep 11:ciaa1371. Epub ahead of print. PMID: 32915202 doi: 10.1093/cid/ciaa1371.
95. Peterson MJ, Giuliani C, Morey MC, et al. Physical activity as a preventative factor for frailty: The health, aging, and body composition study. Journals Gerontol – Ser A Biol Sci Med Sci 2009;64:61–68 https://doi.org/10.1093/gerona/gln001
96. Bonato M, Galli L, Passeri L, et al. A pilot study of brisk walking in sedentary combination antiretroviral treatement (cART)- treated patients: Benefit on soluble and cell inflammatory markers. BMC Infect Dis 2017;17:1–13 https://doi.org/10.1186/s12879-016-2095-9
97. Ceccarelli G, Pinacchio C, Santinelli L, et al. Physical Activity and HIV: Effects on Fitness Status, Metabolism, Inflammation and Immune-Activation. AIDS Behav 2020;24:1042–1050 https://doi.org/10.1007/s10461-019-02510-y
98. Montoya JL, Jankowski CM, O’Brien KK, et al. Evidence-informed practical recommendations for increasing physical activity among persons living with HIV. AIDS 2019;33:931–939 https://doi.org/10.1097/QAD.0000000000002137
99. Wirth MD, Jaggers JR, Dudgeon WD, et al. Association of Markers of Inflammation with Sleep and Physical Activity among People Living with HIV or AIDS HHS Public Access. AIDS Behav 2015;19:1098–1107 https://doi.org/10.1093/gerona/gln001
100. Timmerman KL, Flynn MG, Coen PM, Markofski MM, Pence BD. Exercise training- induced lowering of inflammatory (CD14+CD16+) monocytes: a role in the anti- inflammatory influence of exercise? J Leukoc Biol 2008;84:1271–1278 https://doi.org/10.1189/jlb.0408244
101. Parsons TJ, Sartini C, Welsh P, et al. Physical Activity, Sedentary Behavior, and Inflammatory and Hemostatic Markers in Men. Med Sci Sports Exerc 2017;49:459– 465 https://doi.org/10.1249/MSS.0000000000001113
102. Beavers KM, Brinkley TE, Nicklas BJ. Effect of exercise training on chronic inflammation. Clin Chim Acta 2010;411:785–793 https://doi.org/10.1249/MSS.0b013e3181e3ac80
103. Burke GL, Arnold AM, Bild DE, et al. Factors associated with healthy aging: The Cardiovascular Health Study. J Am Geriatr Soc 2001;49:254–262
104. Hsu FC, Kritchevsky SB, Liu Y, et al. Association between inflammatory components and physical function in the health, aging, and body composition study: A principal component analysis approach. Journals Gerontol – Ser A Biol Sci Med Sci 2009;64:581–589 https://doi.org/10.1093/gerona/glp005
105. Reuben DB, Judd-Hamilton L, Harris TB, Seeman TE. The associations between physical activity and inflammatory markers in high-functioning older persons: MacArthur studies of successful aging. J Am Geriatr Soc 2003;51:1125–1130 https://doi.org/10.1046/j.1532-5415.2003.51380.x
106. Ibeneme SC, Omeje C, Myezwa H, et al. Effects of physical exercises on inflammatory biomarkers and cardiopulmonary function in patients living with HIV: A systematic review with meta-analysis. BMC Infect Dis 2019;19:1–22 https://doi.org/10.1186/s12879-019-3960-0
107. Zech P, Chaparro CGAP, Schuch F, Wolfarth B, Rapp M, Heiβel A. Effects of aerobic and resistance exercise alone or combined on strength and hormone outcomes for people living with HIV:A meta-analysis. J. Assoc. Nurses AIDS Care 2019;30:186-205 https://doi.org/10.1371/journal.pone.0203384
108. Kohut ML, Mccann DA, Russell DW, et al. Aerobic exercise, but not Xexibility/ resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of-blockers, BMI, and psychosocial factors in older adults. Brain Behav Immun 2006;20:201–209 https://doi.org/10.1016/j.bbi.2005.12.002
109. Menshikova E V., Ritov VB, Fairfull L, Ferrell RE, Kelley DE, Goodpaster BH. Effects of exercise on mitochondrial content and function in aging human skeletal muscle. Journals Gerontol – Ser A Biol Sci Med Sci 2006;61:534–540 https://doi.org/10.1093/gerona/61.6.534
110. Broskey NT, Greggio C, Boss A, et al. Skeletal muscle mitochondria in the elderly: Effects of physical fitness and exercise training. J Clin Endocrinol Metab 2014;99:1852–1861 https://doi.org/10.1210/jc.2013-3983
111. Shikuma CM, Hetzler RK, Chow DC, et al. Short Communication: HIV Patient Systemic Mitochondrial Respiration Improves with Exercise. AIDS Res Hum Retroviruses 2017;33:1035–1037 https://doi.org/10.1089/aid.2016.0287
112. Campbell JP, Turner JE. Debunking the myth of exercise-induced immune suppression: Redefining the impact of exercise on immunological health across the lifespan. Front Immunol 2018;9:1–21 https://doi.org/10.3389/fimmu.2018.00648
113. Pascoe AR, Fiatarone Singh MA, Edwards KM. The effects of exercise on vaccination responses: A review of chronic and acute exercise interventions in humans. Brain Behav Immun 2014;39:33–41 https://doi.org/10.1016/j.bbi.2013.10.003
114. Campbell SC, Wisniewski PJ, Noji M, et al. The effect of diet and exercise on intestinal integrity and microbial diversity in mice. PLoS One 2016;11:1–17 https://doi.org/10.1371/journal.pone.0150502
115. Prior SJ, Ryan AS, Stevenson TG, Goldberg AP. Metabolic inflexibility during submaximal aerobic exercise is associated with glucose intolerance in obese older adults. Obesity 2014;22:451–457 https://doi.org/10.1002/oby.20609
116. Helderman JH. Role of insulin in the intermediary metabolism of the activated thymic-derived lymphocyte. J Clin Invest 1981;67:1636–1642 https://doi.org/10.1172/JCI110199
117. Melo BP, Guariglia DA, Pedro RE, et al. Combined exercise modulates cortisol, testosterone, and immunoglobulin A levels in individuals living with HIV/AIDS. J Phys Act Heal 2019;16:993–999 https://doi.org/10.1123/jpah.2019-0134
118. Bonato M, Turrini F, Galli L, Banfi G, Cinque P. The role of physical activity for the management of sarcopenia in people living with HIV. Int J Environ Res Public Health 2020;17 https://doi.org/10.3390/ijerph17041283
119. Piggott DA, Erlandson KM, Yarasheski KE. Frailty in HIV: Epidemiology, Biology, Measurement, Interventions, and Research Needs. Curr HIV/AIDS Rep 2016;13:340–348