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, email@example.com, 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.
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