Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty

Abstract

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age.

Aging and the Adipose Organ

Aging is the leading risk factor for multiple chronic diseases and declines in physical function (60). In many cases, overt disease and disability are preceded by perturbations in metabolic homeostasis and inflammatory status. Adipose tissue is a dynamic organ system that plays a role in modulating systemic metabolism and inflammation (110, 118, 120). In early life, adipose tissue is highly adaptable to environmental changes due to its ability to rapidly alter its endocrine, inflammatory, and metabolic functions (86). This dynamic nature likely evolved as a means of responding to nutrient deprivation, cold-exposure, and/or infection. The rapidity and magnitude of these compensatory effects often vary by adipose depot and change with advancing age and health status. This depot-specific malleability can also promote deleterious effects when age-related changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory state of adipose tissue (118), which we will refer to as adipose tissue dysfunction in this review. The mechanisms responsible for adipose tissue dysfunction are multifactorial and can have secondary physiological effects on a variety of organ systems including liver, muscle, pancreas, and others. Perhaps more importantly, adipose tissue dysfunction is linked with dyslipidemia, metabolic declines, and chronic low-grade systemic inflammation (118), all of which are predictors of impaired physical function and frailty onset (82). Several dietary and pharmacological interventions that extend health span and longevity also delay or prevent adipose tissue dysfunction (37, 78, 111, 130). Furthermore, genetic manipulations that slow aging processes often prevent the pathophysiological mechanisms that promote visceral adiposity, ectopic lipid deposition, and metabolic disturbances (13, 15, 112, 114, 122). Given the role that age-related lipid redistribution plays in the development of systemic insulin resistance, chronic low-grade inflammation, and physical function declines (11, 92), it seems plausible that adipose tissue dysfunction may be a predictor of frailty and declining health span. Here, we will review the connections among adipose tissue dysfunction and systemic declines that lead to the onset of diabetes and frailty.

Mechanisms of Adipose Tissue Dysfunction with Aging

Adipose tissue is comprised of a variety of cell types. The density and function of these cells change throughout life (118). Preadipocytes, also known as adipose-derived stem cells, are one of the most abundant cell types in adipose tissue. Preadipocyte differentiation capacity often declines in aged rodents and humans (20, 57, 58, 61). This is particularly evident in subcutaneous depots where the vast majority of lipid is stored in healthy mammals (19, 118, 120). These perturbations likely contribute to increased central adiposity and ectopic lipid accumulation that are often observed with advancing age (38, 67, 84). Several studies have reported that age-related declines in preadipocyte differentiation are related to reduced CCAAT/enhancer-binding protein alpha (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ) expression and activity (53, 57, 101). Among the causes are increased activity of CCAAT/enhancer-binding protein beta liver-inhibitory protein (C/EBPβ-LIP) and CCAAT/enhancer-binding protein homologous protein (CHOP), which have been shown to form heterodimers with transcriptional regulators that drive adipogenesis (58, 98, 119), thereby impeding the differentiation cascade. Both C/EBPβ-LIP and CHOP expression are increased with aging in preadipocytes, adipocytes, and intact adipose tissue (58, 119) (FIGURE 1). C/EBPb-LIP and CHOP are induced by cellular stress responses such as metabolic dysfunction and inflammatory insults (58, 118, 119). Several reports indicate that the preservation and/or restoration of preadipocyte function in late life can prevent the secondary effects of adipose tissue dysfunction, including lipid redistribution and metabolic perturbations, possibly despite increased adiposity (5, 114, 129). A common theme in most of these models is that they are protected from low-grade inflammation, which undoubtedly plays a role in regulating the differentiation process (48, 54).

FIGURE 1.

Age-related adipose tissue dysfunction drives metabolic and functional declines leading to chronic disease and frailty

Advancing age induces adipose tissue dysfunction, including reduced function of preadipocytes, exacerbated secretion of pro-inflammatory cytokines and chemokines, increased infiltration of immune cells, elevated senescent cell burden, and an increase in the senescence-associated secretory phenotype (SASP). This age-related adipose tissue dysfunction leads to adipose redistribution, local and systemic insulin resistance, and chronic sterile inflammation. Without intervention this can induce systemic metabolic dysregulation and functional decline, eventually leading to diabetes and frailty.

Chronic low-grade inflammation is a hallmark of aging and is linked with the onset of diabetes and frailty (72, 90). Adipose tissue is believed to be a major contributor to systemic inflammation with advancing age (108, 127). Adipose-derived pro-inflammatory cytokines and chemokines arise from a variety of sources in aged mammals. Several reports indicate that preadipocytes can develop expression and secretory phenotypes reminiscent of activated macrophages (23, 25, 77, 133). This process is exacerbated by aging (19, 117), likely due to cellular stress responses brought about by lipotoxicity, hypoxia, and/or replicative arrest (45, 77, 118). Aging also promotes immune cell infiltration into adipose tissue (43, 76), although the magnitude of infiltration and phenotype of cells appear distinct from those observed with obesity (43) (FIGURE 2). Although lesser than what is observed with obesity, activated macrophages are increased in aged adipose tissue and likely contribute to the pro-inflammatory milieu (76). However, their contribution to the pro-inflammatory environment may be less than that of inflamed preadipocytes (118). Aging also leads to increased adipose tissue T-cell populations, particularly in visceral adipose tissue (76). The role of these cells in age-related adipose tissue inflammatory processes remains unresolved, but it is surmised they may dictate immune cell migration given their association with the size of fat-associated lymphoid clusters (43, 85).

FIGURE 2.

Age and obesity synergistically and independently lead to adipose tissue dysfunction, ultimately resulting in metabolic dysfunction and diabetes

Advancing age and obesity are associated with adipose tissue dysfunction and a chronic subclinical pro-inflammatory state. The pathophysiological processes related to adipose tissue dysfunction in aging and obesity are somewhat independent: for example, although immune cell infiltration of adipose tissue occurs with both obesity and aging, macrophage infiltration is more prominent in obesity, whereas T-regulatory cell accumulation is more prominent in aging. The mechanisms underlying adipose tissue dysfunction drive cellular and molecular processes associated with accelerated aging, including activation of the kinases IκB kinase-β (IKKβ) and JUN NH₂-terminal kinase (JNK), elevated pro-inflammatory cytokines, accumulation of senescent cells and increase in senescence-associated secretory phenotype (SASP), increased DNA damage, and oxidative stress. These biological aging processes result in local and systemic dysfunction, ultimately contributing to metabolic dysregulation, insulin resistance, and diabetes.

More recently, adipose tissue dysfunction has been linked to the accumulation of senescent cells (113, 114, 118, 129). Cellular senescence is an irreversible cell-cycle arrest that can be induced by telomere shortening, DNA damage, oncogene activation, and/or metabolic stress (18, 79, 87, 121). Senescent cells are highly pro-inflammatory and develop a phenotype described as the senescence-associated secretory phenotype (SASP) (29, 30). The SASP is comprised of cytokines, chemokines, matrix metalloproteinases, and growth factors, all of which can adversely affect the local microenvironment in adipose tissue by promoting preadipocyte inflammatory processes, inhibiting differentiation, and driving immune cell infiltration (118, 121, 129). The removal of senescent cells through genetic approaches has been found to preserve adipose tissue function, prevent age-related lipid redistribution, enhance vascular activity, and improve systemic metabolic parameters (4, 5, 99, 129). Additionally, pharmacological interventions that reduce senescent cell accumulation (senolytics) and/or suppress the SASP (SASP inhibitors) also elicit beneficial effects on preadipocyte differentiation capacity, adipose tissue insulin-sensitivity, and health span (129, 130, 132). Directly targeting senescent cells through the use of senolytic drugs has begun to show promise (22, 99, 131, 132) and may be the future for treating age-related chronic diseases, such as inflammatory disorders and diabetes (62, 91) (FIGURE 3).

FIGURE 3.

Synergistic effects of adipose tissue dysfunction, cellular senescence, and pro-inflammatory state leads to decline in physical function and frailty

Adipose tissue dysfunction and lipid redistribution, chronic sterile inflammation, and cellular senescence jointly contribute to muscle pathology and reduced contractile function, motor impairment, and physical dysfunction that may ultimately contribute to frailty. Co-incident insulin resistance and diabetes resulting from age-related adipose tissue dysfunction may further exacerbate declines and increase risk of frailty.

Adipose Tissue Dysfunction Promotes Metabolic Declines with Aging

Adipose tissue dysfunction is closely associated with lipid redistribution and chronic low-grade inflammation observed with advancing age (67, 83, 84). These conditions contribute to increased risk for metabolic perturbations such as insulin resistance, impaired glucose tolerance, and diabetes (83, 84). In U.S. adults over 65 years of age, diabetes prevalence varies from 22% to 33%, and the onset is clearly linked to regional adiposity, dyslipidemia, and inflammatory status (38, 63). The connections between diabetes and related comorbidities are well recognized (68, 116), although the pathophysiological mechanisms by which aging promotes insulin resistance and diabetes are only recently garnering attention. Interactions among aging, diabetes, and obesity are particularly interesting, since both diabetes and obesity are arguably conditions that elicit accelerated aging-like phenotypes (51, 81).

Obesity is a well known risk factor for progression of insulin resistance to diabetes, but aging, independently from obesity, may increase the risk of these chronic metabolic conditions through adipose tissue dysfunction, immunological changes, senescent cell accumulation, and pro-inflammatory pathways (70, 110, 118). Epidemiological evidence in middle-aged and older men or women reveals that even subclinical but elevated levels of circulating pro-inflammatory mediators, such as CRP, IL-6, and IL-1β, increase the risk of developing insulin resistance and diabetes (8, 49, 94, 95). Many of these relationships remain significant, although attenuated, after adjusting for obesity or body mass index (BMI). A series of examinations in middle-aged and older adults from the Atherosclerosis Risk in Communities (ARIC) Study support these findings (31, 32, 102). More recently, a case-cohort investigation from the ARIC found that, although older obese individuals had a sixfold greater risk of developing diabetes, the strength of the obesity-diabetes relation dropped by >50% after accounting for seven inflammatory markers: IL-6, CRP, orosoumucoid, sialic acid, white cell count, fibrinogen, and adiponectin (74). Collectively, these data implicate chronic, sterile inflammation in the interactions among obesity, insulin resistance, and diabetes in the context of aging in humans.

Mechanisms of Insulin Resistance and Diabetes with Aging

Mechanisms that underlie the clinical and epidemiological observations linking advancing age to insulin resistance and diabetes are multifactorial. Although mechanisms related to obesity may accelerate aging phenotypes in adipose tissue, aging per se can drive mechanistic pathways both independently and synergistically with obesity (3). For example, aging is associated with a pro-inflammatory state in metabolic tissues and upregulation of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1 family members, which can directly interfere with the insulin-signaling pathway and drive metabolic dysfunction (6, 55, 64, 73, 80, 88, 109). Although substantial evidence clearly implicates a mechanistic role for pro-inflammatory cytokines and the inflammasome on direct and indirect modulation of cellular and systemic insulin resistance, much of the in vivo work has been conducted in rodent models of obesity and diabetes (6, 52, 64, 80, 103, 109). Furthermore, several of the metabolic stressors that promote the common pathology of obesity, insulin resistance, and diabetes also activate the kinases IκB kinase-β (IKKβ) and JUN NH₂-terminal kinase (JNK). These protein kinases are induced in response to inflammation and stress (104), and may be relevant to aging. However, investigations into mechanisms specific to age-related increases in pro-inflammatory status on adipose tissue dysfunction and insulin resistance have received less attention. This distinction could be important, since recent evidence suggests that, although chronic inflammation in dysfunctional adipose tissue is well documented in the pathophysiology of insulin resistance in obesity (128), age-related insulin resistance may be differentially regulated. Macrophage-driven inflammation is a key mechanism underlying insulin resistance in obesity (33, 89), but mechanisms contributing to insulin resistance with aging may differ physiologically. In a murine model, fat-resident regulatory T cells accumulate in dysfunctional adipose tissue with aging, but not in obesity, and mice deficient in these cells do not display age-associated insulin resistance but remain susceptible to obesity-associated insulin resistance and metabolic dysfunction (7). Visceral adipose tissue regulatory T cells may have a significant role in regulating local and systemic inflammation and metabolic processes differentially in obese vs. lean mice (35), and differential accumulation may be dependent on the presence of specific antigens and cytokines (notably IL-33) (66). Thus there may be distinct immune cell populations in visceral adipose tissue in aging from those in obesity. The processes driving metabolic dysregulation in aging and obesity may not be identical.

In an investigation into the shared cellular pathways of aging and obesity on metabolic dysregulation, Minamino et al. examined adipose tissues from genetically obese mice and found biomarkers of accelerated aging, including elevated levels of ROS and DNA damage, as well as higher expression of markers of cellular senescence, including senescence-associated β-galactosidase (SA β-gal), p53, and cyclin-dependent kinase inhibitor 1A (Cdkn1a) (81). Furthermore, p53 inhibition in these mice alleviated inflammation and improved insulin sensitivity, whereas transgenic overexpression of p53 and Cdkn1a, or p53 activation through telomere shortening, increased inflammation and insulin resistance in adipose tissue (81). Collectively, these data implicate cellular aging of adipose tissue, and in particular the p53 tumor suppressor pathway and adipose tissue cellular senescence in the regulation of insulin resistance (3). Cellular senescence may be central to the pathogenesis of age-related insulin resistance and diabetes (91, 118, 129), which could arguably precede immune cell infiltration.

Aging, Physical Function, and Frailty

Aging is characterized by the diminished capacity to respond to stressors and return to homeostasis. As such, aging is the major risk factor for a myriad of diseases and interrelated chronic geriatric conditions, including frailty. Frailty is a geriatric syndrome associated with increased vulnerability following a stress, which increases the risk of adverse outcomes, such as falls, delirium, and disability (1, 27, 41, 42, 106). It is estimated that roughly 25-50% of persons over the age of 85 years are frail (27, 106), which may have substantial consequences not only for human health but also costs associated with the burden of long-term care. A clinical definition of frailty is not fully agreed upon, but most working definitions of the frailty phenotype include declines in physical function and body composition, including unintentional weight loss or loss of muscle mass, muscle weakness, exhaustion or poor endurance, slow walking speed, and low physical activity (41), which result in reduced overall physiological reserve. Perhaps causally related are the age-related changes in muscle pathology that often result in motor unit impairments (declines in contractile velocity and force production) and declines in physical function needed for mobility, balance, strength, and endurance (97). The preservation of physical function is critically important for independent living, and age-related declines in physical function are predictive of high rates of disability and mortality (46, 47, 71, 115). Progressive declines in physical function are principal factors associated with frailty, and there appears to be shared etiology between development of age-related physical dysfunction and frailty.

Epidemiological evidence indicates a link between inflammation and declines in physical function and/or frailty. For example, serum IL-6 is independently related to functional status and impaired walking ability in older adults (14, 34). Furthermore, inflammatory cytokines are associated with several of the individual components of frailty in older adults, including physical dysfunction, and associations between frailty syndrome and inflammation persist even in the absence of common age-related diseases (126). Indeed, a pro-inflammatory state is hypothesized to be at the center of a dynamic model of declines in physical function and physiological processes leading to frailty (40). Given that adipose tissue is a rich source of inflammatory cytokines, it is plausible that age-related adipose tissue dysfunction could be one factor contributing to the systemic pro-inflammatory state associated with these functional declines. Although limited epidemiological evidence exists describing the role of adipose tissue dysfunction in the relationship between chronic, sterile inflammation and physical dysfunction in the absence of obesity or metabolic decline, redistribution of lipid, particularly infiltration into muscle, is associated with motor impairment and declining physical function in older adults (11, 125).

Mechanisms of Physical Dysfunction and Frailty with Aging

The mechanisms by which age-related adipose tissue dysfunction and pro-inflammatory status promote declines in physical function and frailty are incompletely understood. Despite extensive examination of the biomechanical and biological mechanisms linking adipose tissue to declines in physical function, the overwhelming emphasis has previously been placed on the role of excess adiposity, obesity, and sarcopenic obesity (9, 21, 123), and not age-related adipose tissue dysfunction, as emphasized in this review. This distinction is important because, although there are strong associations between greater adiposity and decline in physical function in older adults, these are not entirely explained by potential covariates, including physical activity, chronic diseases, lower muscle mass, or even age. This suggests that there may be effects of adipose tissue itself on the molecular, structural, and metabolic properties of muscle contributing to functional decline (24).

Redistribution of lipid due to adipose tissue dysfunction may lead to age-related functional declines. As previously indicated, advancing age results in an increase in lipid infiltration into muscle, including intermuscular adipocytes along with intramuscular (within muscle but between fibers) and intramyocellular lipid accumulation (10), which have been implicated in functional impairments in older adults (11, 125). There is a strong inverse relationship between the number and size of myofiber lipid droplets and loss of contraction speed and power generation of single muscle fibers from older adults in vitro, and these likely contribute to reduced muscle force and power development observed in the same subjects in vivo (24). Thus there are links between amount and location of fat and muscle function at the cellular and systemic levels in older adults, and these impairments could limit functional ability important for mobility (124). Such effects on function are further compounded when accompanied by sedentary behavior, since muscular lipid redistribution and physical inactivity can exacerbate lipotoxicity and blunt anabolic signaling within muscles (50).

Additionally, several studies in rodents and culture systems suggest that pro-inflammatory cytokines may be implicated in muscle atrophy and/or functional declines. For instance, TNF-α, IL-1β, and IL-6 detected in skeletal muscle can predict declines in grip strength, locomotor ability, and endurance in aged animals (56). Additional studies report that chronic inflammatory disease states lead to pronounced catabolic effects in various tissues, leading to skeletal muscle atrophy (107, 134). Additionally, chronic activation of nuclear factor-κB (NF-κB), a transcription factor central to the classical signaling pathway inducing expression of pro-inflammatory cytokines, can promote muscle atrophy (17), whereas targeted ablation of an NF-κB-activating enzyme can improve muscle strength, mass, and regeneration (86). Systemically, low-grade and persistent inflammation can also interfere with anabolic signaling since IL-6 and TNF-α can downregulate insulin, IGF-1, and erythropoietin signaling, in addition to protein synthesis after a meal or exercise (39). Key insights into the role of inflammatory cytokines in functional decline and frailty can be gleaned from a frail mouse model developed from targeted depletion of IL-10, an important anti-inflammatory cytokine. These mice have increased basal circulating cytokines, including IL-6, IL-1β, and TNF-α, as well as muscle weakness, altered skeletal muscle gene expression, endocrine changes, IGF-1 dysregulation, and increased mortality (65). However, inflammatory dysregulation in this model occurs with much earlier onset, possibly in utero, than would be expected in humans, thereby complicating the translation of findings from this model to older adults (82).

There also may be synergistic effects of inflammation and lipid redistribution on skeletal muscle and possibly physical dysfunction and frailty. In human primary cell culture experiments, the secretory profile of visceral adipose tissue obtained from obese individuals induced a gene and protein expression profile in co-cultured myocytes indicative of muscle atrophy and suppression of key contractile elements. These myocytes had increased secretion of cytokines and chemokines, including IL-1β and IL-6, leading to the conclusion that adipocytes support a pro-inflammatory milieu that is harmful to muscle and may lead to reduced contractile properties and possibly functional decline (93). Although this investigation indicates a unique interaction among adipocytes, inflammation, and muscle, these findings were performed in the context of obesity, not aging, and muscle function was inferred but not measured (59). Thus there may be a direct link between pro-inflammatory secretory profiles from dysfunctional adipose tissue and skeletal muscle, possibly contributing to motor impairment and physical dysfunction, but this area warrants further investigation.

Finally, cellular senescence and the related SASP have been proposed to play an essential role in the development of age-related functional decline and, in particular, the frailty syndrome (69). This contribution could be related to pro-inflammatory signaling cascades, limited capacity to regenerate damaged or atrophied tissues due to restricted regenerative ability of stem cell pools, and impaired tissue functionality (28, 69, 121, 129). Recently, Schafer et al. provided evidence linking cellular senescence to functional decline, demonstrating an association between increased senescent cell biomarkers, the SASP, and worsened physical and metabolic health following a “fast-food diet” (100). Furthermore, exercise prevented the accumulation of senescent cells and alleviated the functional declines that accompanied the diet, providing evidence supporting the value of therapeutic approaches that suppress cellular senescence and the SASP on functional health outcomes.

Relationships Between Diabetes and Frailty

Evidence suggests there may be a link between diabetes and frailty with advancing age. The prevalence of both metabolic dysfunction and frailty increases with advancing age. Interestingly, diabetes and frailty are independently predictive of mortality, but mortality risk is even greater with co-occurrence of frailty and diabetes (16). Moreover, diabetes and frailty may share many pathophysiological mechanisms, including low-grade systemic inflammation, cytokine dysregulation, senescent cell accumulation, and adipose tissue dysfunction. Metabolic dysregulation and insulin resistance in skeletal muscle may exacerbate functional decline and frailty (26). Skeletal muscle is a key peripheral organ responsible for glucose uptake and utilization, and glucose disposal is impaired with insulin resistance (44). This is complicated by the age-related loss of muscle mass. Furthermore, insulin inhibits catabolism in skeletal muscle (2). However, anabolic resistance develops with advancing age and may further affect muscle mass, muscle function, and whole-body glucose homeostasis (96). With the frequent co-occurrence of obesity and insulin resistance and the associated subclinical inflammatory state, these effects are further compounded. In addition to the shared mechanisms already described, possible causes of dysfunction may be related to macrophage infiltration (36), imbalance between M1 and M2 macrophages (12, 75), activation of cellular stress signaling pathways (105), and inflammatory and molecular pathways related to carbohydrate and protein metabolism within muscle (26).

Summary

Adipose tissue is a dynamic organ system responsible for energy storage and nutrient sensing, but it also has a broad range of endocrine and immunological functions. With aging, adipose tissue undergoes dramatic changes in functional capacity, which is implicated in systemic pro-inflammatory status and several other biological hallmarks of aging, including cellular senescence, mitochondrial dysfunction, metabolic declines, and dysregulated nutrient sensing pathways. This cascade of molecular and cellular changes in adipose tissue can drive systemic pathophysiological processes that result in age-related chronic disease such as diabetes, as well as declines in physical function and frailty. In conclusion, adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age. These intimate relationships make therapeutic targeting of adipose tissue an attractive approach to combating age-related diseases and disability as a single entity as opposed to targeting individual conditions one-at-a-time.