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Fat is redistributed in aging with Subcutanfous SAT and increased intra-abdominal visceral depots. A decrease in brown and beige fat leads to thermal dysregulation and energy imbalance. In addition to adipocytes and adipose progenitor cells, other nonadipocyte cells, such as macrophages, fibroblasts, and lymphocytes, are also indispensable components of the stromal vascular fraction SVF and contribute to the hallmarks of aging [ 131415 ].
Due to the decreased inflammatory and coagulant-related gene expression in resident stromal cells of adipose tissue, the elderly population is significantly more susceptible to inflammatory stress [ 16 ]. Elevated cellular senescence and the related senescence-associated secretory phenotype SASP are significant features of aging, which are proposed to play an essential role in the age-related functional decline of adipose tissue [ 17 ].
Extensive research has investigated the underlying biomechanical and biological mechanisms of adipose tissue aging, especially excess adiposity. As a large and dynamic endocrine, immune, and regenerative organ, adipose tissue plays a major role in health via releasing factors that regulate diverse processes, such as appetite control, glucose metabolism, insulin sensitivity, inflammation activity, and tissue repair [ 181920 ].
Increasing adipocyte-secreted endocrine factors affecting adjacent or remote tissues and organs have been identified, with well-recognized leptin and adiponectin selectively expressed in adipocytes [ 22 ]. Due to the dysregulation in endocrine factors, the ability of adipose tissue to buffer excess nutrients is reduced with advancing age, which probably let older people be more prone to obesity [ 23 ].
Moreover, adipose tissue becomes dysfunctional with a dysregulated secretome, including proinflammatory cytokines and hormones, which is correlated with several known age-related disorders.
Adipose tissue-derived substances or stimuli contribute to the widespread presence of chronic inflammation in aging directly or indirectly. Obesity, a common disease generally characterized by abnormal adipose tissue, is supposed to be a state of accelerated aging [ 24 ]. Inflammation and oxidative stress seem to be important mediators of the complicated association between obesity and the aging process.
Interestingly, preclinical and clinical studies show that strategies targeting adipose tissue aging have been shown to mitigate age-associated physical dysfunction and extend health span.
In this review, we discuss how aging impacts fat tissue function and in turn leads to age-related disease, with the related cell biological and molecular mechanisms. Additionally, we discuss the attractive role of aging adipose tissue in aging therapy.
In the process of aging, adipose tissue undergoes dramatic changes in mass and biodistribution. Total fat mass accumulation is common in both healthy and unhealthy elderly individuals and can occur as early as middle age [ 25 ].
However, a decline in fat mass can be found in extremely old stages and may be a sign of deteriorated health [ 25 ]. Another age-related change in body composition is fat redistribution, which is featured by a preferential increase in visceral fat, with a decrease in lower body subcutaneous fat [ 12 ] Fig.
Subcutaneous and visceral adipose depots are very different in terms of their effects on metabolism. In general, SAT is considered beneficial for metabolism, whereas VAT is thought to be harmful. The age-related redistribution of adipose tissue in favor of visceral depots impacts systematic healthy aging.
Thus, fat redistribution during aging is correlated with an increased risk of metabolic abnormalities, particularly insulin resistance accompanied by an increased risk of cardiovascular disease and diabetes [ 2526 ].
There is a redistribution of WAT mass with advancing age, displayed by increased visceral fat and reduced subcutaneous fat.
Yellow represents subcutaneous fat, and red represents visceral fat. The underlying mechanisms of subcutaneous peripheral fat loss during aging are not fully appreciated. It has been suggested that peripheral fat loss in aging is partially due to defects in adipogenesis in SAT, which are related to overactivated inflammation [ 27 ].
In addition, the telomere basal length in subcutaneous fat is shorter than that in visceral fat, suggesting that SAT is more vulnerable to age-related detriment [ 28 ]. Considering the beneficial effects of SAT on systemic metabolism, metabolic dysfunction in aging probably originates from SAT deficiency.
The age-related alterations vary in different depots of adipose tissue, with a significant reduction in BAT and beige fat that are critical thermogenic cells for maintaining body temperature by nonshivering thermogenesis. In general, brown and beige adipocytes enhance their activity to increase energy expenditure, which is thought to resist adipose tissue dysfunction and the development of obesity [ 29 ].
The decline of brown and beige fat occurs in the aging process, which possibly aggravates thermal dysregulation and energy imbalance in elderly individuals [ 3031 ].
The decline in BATs is first detected in interscapular depots during aging. However, deeper depots, particularly perivascular and kidney depots, are lost at a later stage.
The decreased BAT is consistent with the fact that older humans are hard to maintain body temperature. Researchers found that UCP1 and β3AR are associated with age-related reductions in BAT activity [ 32 ]. Increased winged helix factor forkhead box protein A3 FOXA3 expression in aging adipose tissue is also involved in the reduction of BAT [ 33 ].
Increasing BAT by RGS14 knockout or surgical BAT transplantation results in healthful aging with enhanced longevity and metabolism [ 34 ]. It is considerable to take BAT as a therapeutic target for the health of elderly people. Adipose progenitor and stem cells APSCs are the essential stem cell pool in the stromal vascular fraction SVF of adipose tissue and give birth to mature adipocytes.
The differentiation and proliferation potential of APSCs ensures the renewal, expansion, and functional plasticity of adipose tissue. However, the proliferation and differentiation capacity of APSCs gradually declines with increasing age [ 435 ].
In addition to the dramatically slower growth rate of preadipocytes in older individuals, the differentiation of preadipocytes is significantly compromised compared to that in younger individuals.
APSCs obtained from older donors have less osteogenic potential than those obtained from young donors, which suggests that aging APSCs might only have limited suitability for regenerative medicine [ 36 ].
The decline in APSC proliferation is reported to begin at age 30 and is most obvious at age 50 years. APSC dysfunction impairs the plasticity of Subcuhaneous tissue, which may be an underlying mechanism of insulin resistance in elderly individuals [ 37 ].
Furthermore, because preadipocytes are less able to differentiate and properly store lipids, aging adipose tissue exposes other tissues and organs to even greater amounts of lipotoxic free fatty acids [ 38 ].
This lipotoxicity is recognized as a critical mechanism of metabolic syndrome that seriously impacts the quality of life of elderly people.
Several therapeutics targeting APSCs have been developed and have achieved some interesting results. Blocking activin A by JAK inhibition was demonstrated to be a useful strategy for improving senescent APSCs, with restored lipid accumulation and expression of key adipogenic markers [ 39 ].
Fat grafting, which applies the multidirectional differentiation and reproductive activity of adipose-derived progenitors, has been utilized for over years [ 40 ]. Whether and how aging impacts fat grafting in elderly individuals?
How can the stemness of APSCs be enhanced for fat grafting in old patients? These questions require more research to answer. Cellular senescence is a state characterized by cell cycle arrest and is related to a decline in the regenerative potential and function of various tissues, which drive the systematic aging process [ 41 ].
Adipose tissue is a site of massive senescent cell accumulation during aging [ 4243 ] Fig. Senescent cells accumulate in aging fat induced by a combination of replicative, Subxutaneous, and metabolic stresses [ 44 ]. Although cellular senescence is suggested to be a defensive mechanism preventing tumorigenesis, its occurrence in adipose tissue causes multiple dysfunctions, including defective adipogenesis, inflammation, aberrant adipocytokine production, and insulin resistance.
These aging cells secrete the SASP consisting of cytokines, chemokines, proteases, and growth factors, which is considered to be an aging signal [ 3944 ] Fig. The declined stemness and adipogenesis of aged APSCs may also be a result of the accumulation of senescent cells [ 39 ].
A study found that human senescent adipocyte progenitors inhibit adipogenesis of surrounding nonsenescent progenitors via the paracrine pathway [ 39 znd.
When the accumulation of senescent cells is too much to clean, the response of immune cells may be disturbed by chemokines released by senescent cells. In young WAT, APSCs actively proliferate and differentiate to adipocytes. Resident immune cells keep in a relatively stable state.
With advancing aging, APSCs gradually lose their developmental potential, leading to low adipogenesis.
: Subcutaneous fat and aging| Skin aging: are adipocytes the next target? | Aging | Article PubMed PubMed Central Google Scholar Fried SK, Bunkin DA, Greenberg AS. Leptin is a proinflammatory adipokine best known for its role in appetite, satiety, and energy expenditure 62 — To further understand the possible functional implications of these gene expression characteristics, KEGG and GO analyses of these differentially expressed genes were performed. Conditioned medium of senescent macrophages significantly increased PLAU expression level in young human primary APC supplementary Fig. It has long been established that obesity is one of the major risk factors for a range of age-related diseases, including diabetes, cancer, and cardiovascular disease [ ]. |
| Skin aging: are adipocytes the next target? | Article Breakfast for stronger muscles PubMed Central Google Scholar Fried SK, Faf DA, Greenberg AS. Weight increases far age Hydrating and plumping BMI peaks occur in people aged 50—59 years and adipose Breakfast for stronger muscles reaches its peak between Subcutanwous ages of 60 and 79 years. Proc Natl Acad Sci USA. It is becoming increasingly clear that these depots have distinctly different functions. However, since human dWAT structures can spatially reach the upper dermis Fig. Brown adipose tissue is closely associated with the cervical, supraclavicular, and superior mediastinal vasculature in humans The relative enrichment ratios of coding regions, intergenic regions, introns, exons, upstream regions, and downstream regions of the SAT genome at different ages were summarized. |
| Top bar navigation | Weight-reducing effects of the plasma protein encoded by the obese gene. Sex- and menopause-associated changes in body-fat distribution. In light of all these observations, dermal adipocytes may be an effective target in stand-alone and combinational skin anti-aging therapies. Enomoto T, Ohashi K, Shibata R, Higuchi A, Maruyama S, Izumiya Y, et al. B Downregulated gene enrichment in biological processes. Adiponectin and thyroid Cancer: insight into the association between adiponectin and obesity. The characteristics of the study group are shown in Supplemental Tables 1, and whole genome analysis was performed on all samples. |
Subcutaneous fat and aging -
In general, SAT is considered beneficial for metabolism, whereas VAT is thought to be harmful. The age-related redistribution of adipose tissue in favor of visceral depots impacts systematic healthy aging.
Thus, fat redistribution during aging is correlated with an increased risk of metabolic abnormalities, particularly insulin resistance accompanied by an increased risk of cardiovascular disease and diabetes [ 25 , 26 ].
There is a redistribution of WAT mass with advancing age, displayed by increased visceral fat and reduced subcutaneous fat. Yellow represents subcutaneous fat, and red represents visceral fat. The underlying mechanisms of subcutaneous peripheral fat loss during aging are not fully appreciated.
It has been suggested that peripheral fat loss in aging is partially due to defects in adipogenesis in SAT, which are related to overactivated inflammation [ 27 ].
In addition, the telomere basal length in subcutaneous fat is shorter than that in visceral fat, suggesting that SAT is more vulnerable to age-related detriment [ 28 ].
Considering the beneficial effects of SAT on systemic metabolism, metabolic dysfunction in aging probably originates from SAT deficiency. The age-related alterations vary in different depots of adipose tissue, with a significant reduction in BAT and beige fat that are critical thermogenic cells for maintaining body temperature by nonshivering thermogenesis.
In general, brown and beige adipocytes enhance their activity to increase energy expenditure, which is thought to resist adipose tissue dysfunction and the development of obesity [ 29 ]. The decline of brown and beige fat occurs in the aging process, which possibly aggravates thermal dysregulation and energy imbalance in elderly individuals [ 30 , 31 ].
The decline in BATs is first detected in interscapular depots during aging. However, deeper depots, particularly perivascular and kidney depots, are lost at a later stage.
The decreased BAT is consistent with the fact that older humans are hard to maintain body temperature. Researchers found that UCP1 and β3AR are associated with age-related reductions in BAT activity [ 32 ].
Increased winged helix factor forkhead box protein A3 FOXA3 expression in aging adipose tissue is also involved in the reduction of BAT [ 33 ]. Increasing BAT by RGS14 knockout or surgical BAT transplantation results in healthful aging with enhanced longevity and metabolism [ 34 ].
It is considerable to take BAT as a therapeutic target for the health of elderly people. Adipose progenitor and stem cells APSCs are the essential stem cell pool in the stromal vascular fraction SVF of adipose tissue and give birth to mature adipocytes.
The differentiation and proliferation potential of APSCs ensures the renewal, expansion, and functional plasticity of adipose tissue. However, the proliferation and differentiation capacity of APSCs gradually declines with increasing age [ 4 , 35 ].
In addition to the dramatically slower growth rate of preadipocytes in older individuals, the differentiation of preadipocytes is significantly compromised compared to that in younger individuals. APSCs obtained from older donors have less osteogenic potential than those obtained from young donors, which suggests that aging APSCs might only have limited suitability for regenerative medicine [ 36 ].
The decline in APSC proliferation is reported to begin at age 30 and is most obvious at age 50 years. APSC dysfunction impairs the plasticity of adipose tissue, which may be an underlying mechanism of insulin resistance in elderly individuals [ 37 ].
Furthermore, because preadipocytes are less able to differentiate and properly store lipids, aging adipose tissue exposes other tissues and organs to even greater amounts of lipotoxic free fatty acids [ 38 ]. This lipotoxicity is recognized as a critical mechanism of metabolic syndrome that seriously impacts the quality of life of elderly people.
Several therapeutics targeting APSCs have been developed and have achieved some interesting results. Blocking activin A by JAK inhibition was demonstrated to be a useful strategy for improving senescent APSCs, with restored lipid accumulation and expression of key adipogenic markers [ 39 ].
Fat grafting, which applies the multidirectional differentiation and reproductive activity of adipose-derived progenitors, has been utilized for over years [ 40 ]. Whether and how aging impacts fat grafting in elderly individuals? How can the stemness of APSCs be enhanced for fat grafting in old patients?
These questions require more research to answer. Cellular senescence is a state characterized by cell cycle arrest and is related to a decline in the regenerative potential and function of various tissues, which drive the systematic aging process [ 41 ].
Adipose tissue is a site of massive senescent cell accumulation during aging [ 42 , 43 ] Fig. Senescent cells accumulate in aging fat induced by a combination of replicative, cytokine-induced, and metabolic stresses [ 44 ]. Although cellular senescence is suggested to be a defensive mechanism preventing tumorigenesis, its occurrence in adipose tissue causes multiple dysfunctions, including defective adipogenesis, inflammation, aberrant adipocytokine production, and insulin resistance.
These aging cells secrete the SASP consisting of cytokines, chemokines, proteases, and growth factors, which is considered to be an aging signal [ 39 , 44 ] Fig. The declined stemness and adipogenesis of aged APSCs may also be a result of the accumulation of senescent cells [ 39 ].
A study found that human senescent adipocyte progenitors inhibit adipogenesis of surrounding nonsenescent progenitors via the paracrine pathway [ 39 ]. When the accumulation of senescent cells is too much to clean, the response of immune cells may be disturbed by chemokines released by senescent cells.
In young WAT, APSCs actively proliferate and differentiate to adipocytes. Resident immune cells keep in a relatively stable state.
With advancing aging, APSCs gradually lose their developmental potential, leading to low adipogenesis. Aberrant immune cells and senescent cells accumulation drive the aging process of adipose. This figure was created in part with modified BioRender templates.
Abnormal activation of immune cells is a hallmark of aging and is first detected in WAT depots at middle age Fig. WAT harbors a complex combination of immune cells, including lymphocytes, macrophages, and eosinophils.
Various endogenous substances or stress-inducing agents, such as hypoxia and excess nutritional element-related fatty acids, byproducts of cell death, and endoplasmic reticulum ER stressors, may trigger sterile inflammation of adipose tissue to varying degrees.
However, we still lack knowledge about the context of immune cells in aging adipose tissue. Adipose tissue macrophages regulate the age-related decline in adipocyte lipolysis in mice by repressing the bioavailability of noradrenaline, which can be rescued by the deletion of catecholamine degradation genes [ 7 ].
Aged ILC2s are compromised to a proinflammatory and senescence-like state with dysregulated IL expression, ultimately leading to a cold vulnerability in old mice [ 14 ].
Adipose tissue eosinophils undergo major age-related changes in distribution and function with eosinophil-derived IL-4 deficiency [ 46 ]. Fat-resident regulatory T cells increase in aged adipose tissue, which is supposed to regulate adipose tissue insulin sensitivity [ 47 ].
Fat-resident B cell dysfunction with high TNF-α levels has been reported in a previous study, which may lead to an impaired influenza vaccine-specific response in elderly individuals [ 48 ]. The immunosuppressive network in aging is supposed to prevent excessive inflammatory responses, but at the same time, they repress the immune system [ 49 ].
Very few studies have investigated the role of the immunosuppressive network in adipose aging. It is controversial whether the changes in immune cells within aged adipose tissue are a cause or consequence of adipose tissue dysfunction, which needs further investigation.
Resident BAT in adults can be found mostly in the cervical-supraclavicular region and smaller depots located in the axillary, mediastinal, paravertebral, epicardial, and abdominal areas [ 50 ], which is related to poor temperature regulation in elderly individuals.
Several mechanisms are associated with BAT decline with advancing age. Mitochondrial function is impaired in adipose tissue in age, which may be due to the accumulation of mitochondrial DNA mutations, as well as a reduction in oxidative phosphorylation and the expression of the uncoupled activity of protein-1 UCP-1 , a thermogenesis-related mitochondrial protein in brown fat cells [ 51 ].
Since the sympathetic nervous system mediates the activation of BAT at cold temperatures, low sympathetic activity in older individuals may contribute to poor BAT activity [ 52 ]. Increased levels of proinflammatory cytokines in the aging process repress BAT thermogenic capacity by suppressing UCP-1 gene expression [ 53 , 54 ].
Glucocorticoids inhibit adrenergic-stimulated UCP-1 expression, which may contribute to a decline in BAT activity [ 55 , 56 ]. The intervention of hormone levels could be a strategy to preserve, supported by the finding that inhibition of circulating orexigenic hormone Ghrelin by gene editing or antagonist in mice increased thermogenic capacity in brown adipose tissues [ 57 ].
A reduction in beige adipocyte formation is also detected in aging adipose tissue. The age-related reduction in SIRT1, which drives beige adipocyte generation from WAT, maybe one of the key mechanisms in the loss of beige adipose tissue [ 58 ].
A mechanistic understanding of APSC dysfunction with age could help to prevent age-related adipose disorders. Impaired preadipocyte differentiation is linked to altered levels of adipogenic factors Fig. Age-related decline in PPARγ expression in adipose tissue also contributes to impaired adipogenesis during aging [ 61 , 62 ].
Moreover, impaired differentiation capacity during aging is a result, in part, of increased levels of antiadipogenic factors. Thus, inhibition of CUGBP expression in the preadipocytes of elderly persons may help to improve adipogenesis. As a result, old APSCs show a decline in proliferation and differentiation, which leads to low adipogenesis in the elderly.
In addition to transcription factors, microRNAs miRNAs and short 17—20 nts noncoding RNAs are also involved in preadipocyte dysfunction during the aging process by regulating transcription and mRNA translation in adipogenic pathways. Age-associated differentiation defects of preadipocytes with aging are found to be correlated with miR, which promotes adipocyte differentiation via the ERK5-PPARγ pathway [ 62 , 65 ].
Together, the key genes whose expression level correlated with age in preadipocytes are potential targets to rejuvenate preadipocytes in elderly individuals. Senescent cell accumulation can be induced by various endogenous and exogenous stresses, including DNA damage, telomere shortening, oncogenic mutations e.
Consistent with the notion that cellular senescence is an important mechanism for preventing cancer progression, the P53 and pRB tumor pathways are central regulators of senescent cell accumulation [ 67 ].
Inhibition of P53 has been shown to induce senescent cells to reenter the cell cycle [ 68 , 69 ]. Chronic inflammation with continued upregulation of proinflammatory mediators e.
SASP factors derived from senescent cells in adipose tissue contribute to proinflammatory factors cytokines, chemokines, and microRNAs , TNF receptors, nonprotein soluble factors nitric oxide , growth factors EGF, VEGF, and NGF , and extracellular matrix macromolecules fibronectin, collagens, and laminin in the microenvironment [ 43 , 71 ].
The role of the SASP may not be limited to impacting tissue structure and function directly or indirectly.
SASP factors such as IL-6, IL-8, GROα, and IGFBP-7 participate in an autocrine feedback loop to reinforce growth arrest in senescent cells for tumor suppression [ 72 ]. In addition, the SASP might recruit an infiltrating immune response to clear senescent cells [ 73 ].
Several molecular mechanisms have been demonstrated to participate in SASP regulation, which could be potential targets for age-related therapy. Since the roles of cell senescence and the SASP in aging are complicated, future studies need to precisely elucidate the deleterious effects of the SASP and cell senescence.
Chronic inflammation characterized by continued proinflammatory factor secretion at levels higher than baseline contributes to general aging and age-related diseases [ 76 ]. Fat tissue, especially preadipocytes, has been suggested to be a major source of inflammatory cytokines during aging.
A previous study reported that adipose tissue in old mice expresses higher levels of proinflammatory cytokines, including IL-1, IL-6, TNF-α, and the hallmark lipid inflammatory mediator cyclooxygenase 2 COX-2 , and lower levels of anti-inflammatory PPAR-gamma than those of young mice [ 76 ].
Another aging study found that genes of cytokine-mediated inflammatory pathways, including Ccl8, show significantly upregulated expression in GAT at 18 months [ 3 ]. Proinflammatory cytokine release from preadipocytes under TNF-α exposure drives adjacent cells into a proinflammatory state, in parallel with promoting endothelial cell-monocyte adhesion and macrophage infiltration [ 77 ].
Age-related activation of inflammatory cytokines and chemokine expression in adipose tissue vary among different depots, e.
Although age-related changes in the fat tissue inflammatory environment are similar to those in obesity, the inflammatory expansion and activation of macrophages in aging seem less impressive than those in obesity [ 79 ].
The response of macrophages to shift into a proinflammatory state by chemokines and cytokines generally declines with aging [ 80 ].
Several mechanisms have been shown to induce inflammation with aging. Dysregulated autophagy activity in aging adipose tissue promotes age-related high elevated endoplasmic reticulum ER stress and inflammation, which may be linked to the accumulation of autophagy substrates LC3-II and p62 [ 81 ].
The ER stress response in aging adipose tissue promotes age-associated inflammation, which can be attenuated by chemical chaperones [ 6 ]. Since dysregulated adipokines from adipose tissue can contribute to chronic low-grade inflammation in obesity, adipokines may also play a role in age-related inflammation [ 23 ].
Several age-related changes in adipose tissue have been supposed to be the endogenic reason for metabolic dysfunction. Adipocyte hypertrophy with inefficient nutrient transport and poor cell signaling, which is a common feature of aging, may lead to metabolic defects and decreased energy expenditure [ 82 ].
Age-related changes in the adipose tissue extracellular matrix, such as decreased periostin and collagen VI, may lead to metabolic defects by negatively affecting nutrient and energy homeostasis [ 83 , 84 ]. Ablation of the gene encoding periostin in mice leads to age-related metabolic dysfunction with a low adaptation of adipose tissue to adrenergic stimulation and high-fat diet feeding, as well as lipid metabolism in adipose tissue [ 83 ].
Cellular senescence in adipose tissue probably participates in metabolic dysfunction, which is supported by the finding that inhibition of p53 activity in adipose tissue markedly improved insulin resistance [ 85 ].
Consistently, inhibition of senescent cells or their products in adipose tissue has been shown to improve metabolism in old mice [ 39 ]. Accumulating evidence indicates that age-related alterations in adipose tissue contribute to insulin resistance in the elderly population.
Age-related defects in the insulin signaling cascade, such as a reduction in insulin-stimulated tyrosine phosphorylation, are more severe in adipose tissue than in either the liver or muscle, which suggests that adipose tissue may be an origin of insulin resistance during the aging process [ 86 ].
Lipid redistribution and chronic inflammation derived from aging adipose tissue induce metabolic perturbation, including insulin resistance, impaired glucose tolerance, and diabetes.
High levels of proinflammatory cytokines, such as IL-1 family members, in dysfunctional adipose tissue may directly disturb the insulin signaling pathway [ 87 , 88 ]. In addition, age-related alteration of immune cells, such as T cell accumulation, maybe one of the causes of insulin resistance [ 47 ].
With the widespread communication between adipose tissue and nonadipose tissue, altered adipose tissues impact the metabolism of other organs and tissue via several pathways. Both the thermogenesis activity and total mass of brown and beige adipose tissue decline with advancing age, which contributes to decreased energy consumption in the elderly population.
Impaired cold exposure-stimulated thermogenesis of BAT also causes age-associated cold sensitivity. Since BAT regulates whole-body glucose and energy homeostasis via consuming fuels such as glucose and lipids, a decline in BAT in aging can cause a preference for metabolic disease [ 89 ].
In addition, BAT dysfunction disturbs the metabolism of other tissues with altered secretion, which mediates the conversation between different organs. As 12,diHOME acts as a paracrine signal to promote skeletal muscle fatty acid uptake and oxidation, decreased 12,diHOME from BAT in old mice may counteract energy consumption under conditions such as cold exposure or exercise [ 90 , 91 ].
It has been reported that the accumulation of perimuscular adipose tissue, which is ectopic fat deposition surrounding atrophied muscle, promotes age-related muscle atrophy by increasing proteolysis and in muscle [ 92 ].
The breakdown and release of lipids in aging due to lack of lipid-storing adipocytes and decreased lipolysis in impaired WAT lead to lipotoxicity on other tissue [ 5 ]. For instance, ectopic lipid accumulation in the liver may accelerate the development of nonalcoholic fatty liver disease during aging [ 93 ].
In addition, age-related redistribution of white adipose tissue, especially with excessive adipose tissue mass in visceral, intermuscular, and intramuscular depots, exacerbates system-wide metabolic dysfunction.
Increased visceral adipose mass, which can impair the liver with free fatty acids and proinflammatory factors, may be particularly involved in the pathogenesis of insulin resistance and type 2 diabetes [ 94 ]. Together, metabolic defects both locally and systematically caused by adipose tissue ultimately make older people more susceptible to various metabolic diseases.
Adipose tissue is an important endocrine organ that releases adipokines, such as leptin, adiponectin, and resistin, that are signals to target other tissues and organs [ 95 ].
The abnormal adipokine levels released from either adipocytes or adipose tissue-infiltrated macrophages in aging serve to the chronic inflammatory environment and insulin resistance, which could be a risk factor for cardiovascular disease in elderly individuals.
Impaired leptin-mediated regulation with leptin resistance, which probably results from high plasma leptin levels and declined WAT, induces abnormal hypothalamus-related activity and elevated obesity and serum leptin with age [ 97 , 98 ]. The correlation of leptin levels with liver diseases, such as cirrhosis and fibrosis, supports that leptin may mediate the pernicious influence of abnormal adipose tissue on the liver [ 99 , , ].
Adiponectin, an adipocyte-derived sensitizer of insulin signaling, and its downstream factors have been implicated in insulin signaling, which is vulnerable to aging [ 98 ]. Adiponectin reduces the triglyceride content in skeletal muscle by increasing molecules involved in fatty acid translocation to protect insulin-stimulated phosphatidylinositol PI 3-kinase activation and glucose metabolism, which is required for proper insulin signaling [ ].
Dysregulation of adiponectin in older individuals is related to aging-associated chronic diseases, which might be a potential target for aging therapy [ ]. Adipocyte-derived resistin antagonizes insulin signaling, in parallel with decreasing glucose intake in adipocytes, muscle cells, and other tissues.
Resistin induces increased permeability and superoxide anion production in coronary artery endothelial cells, which may contribute to vascular lesion formation and subsequent vascular disease [ ].
In brief, dysregulated adipokines due to age-related alterations may spread the aging signal and accelerate the aging process. In the process of aging, high circulating levels of proinflammatory cytokines derived from adipose tissue are regarded as major contributors to systemic, chronic low-grade inflammation.
High levels of IL-6 and MCP-1 from preadipocytes responding to ER stress in aging are inflammatory cytokines that have broad effects on elderly individuals [ 6 ].
As adipose macrophage content has been shown to positively correlate with aging, macrophage-derived NLRP3 inflammasomes may cooperate with activated T cells to induce the development of inflammation in adipose tissue and the liver [ , ].
Since TNF-α is an essential proinflammatory cytokine that drives the inflammatory process, whether dysfunctional adipose tissue induces systemic inflammation by secreting TNF-α in aging may need further investigation [ , ].
Harmful products produced by dysregulated adipose tissue, such as lipids and free fatty acids, are also driving factors of inflammation [ 7 ]. Increased systemic free fatty acids, especially saturated fatty acids, promote the binding of monocytes to endothelial cells and proatherogenic cell surface antigen expression, which is a risk factor for atherosclerosis [ , , ].
MiRNAs are small noncoding RNAs with 19—22 nucleotides that play critical roles in regulating mRNA metabolism.
Circulating miRNAs are present in the extracellular environment, of which a large proportion are wrapped in exosomes [ ].
In addition to being recognized as biomarkers [ ], miRNAs in systemic circulation could regulate the gene expression and function of distal cells by mediating paracrine and endocrine communication between different tissues. Adipose tissue has been demonstrated to be a crucial source of circulating miRNA, which may be involved in the communication between adipose tissue and other tissues.
For instance, mouse miRb derived from BAT regulates FGF21 expression in the liver [ ]. Decreased miRNA biogenesis due to the downregulation of Dicer and miRNA processing occurs at the level of the whole organism, including adipose tissue [ ].
Interestingly, the beneficial effects of caloric restriction on the aging process rely on appropriate miRNAs from fat tissue, which may include circulating miRNAs [ ]. To apply adipose-derived miRNAs for aging therapy, we still need more future studies to identify detailed miRNAs released from adipose tissue.
It has long been established that obesity is one of the major risk factors for a range of age-related diseases, including diabetes, cancer, and cardiovascular disease [ ]. There are many causes of obesity, including genetic mutation, physical inactivity, and malnutrition, with the common result of abnormal accumulation of fat tissue.
Obesity-related adipocyte hyperplasia in visceral white adipose tissue, which occurs more often in males than in females, may drive the age-associated redistribution of adipose tissue [ ]. Obesity has been shown to accelerate the aging process in the liver, with nuclear mitochondrial genes involved in phosphorylation and electron transport [ ].
In obesity, the excess presence of ROS due to fat accumulation increased Gfi1 expression in hematopoietic stem cells, which is associated with age-related hematological disorders [ , , ]. Increased retinol-binding protein-4 RBP4 in obesity downregulates phosphatidylinositolOH kinase PI 3 K signaling in muscle and promotes gluconeogenic enzyme phosphoenolpyruvate carboxykinase expression in the liver through a retinol-dependent mechanism, which induces insulin resistance [ ].
For cardiovascular disease, studies have revealed a significant association between obesity and elevated blood pressure, with obese individuals being 3. Obesity-induced adipose tissue inflammation may be a driver of cancer risk, and certain adipokines e.
Since obesity and the aging process share many pathogeneses and phenotypes, including impaired mitochondrial function, abnormal immunity, elevated systemic inflammation, and insulin resistance, interventions for obesity could slow down the aging process.
Recently, a large-scale targeted proteomic analysis of a diverse panel of young versus old murine tissues revealed a significant aging effect on white adipose tissue, with alterations in lipid metabolism, central carbon metabolism, electron transport chain complexes, and inflammation [ ].
Another bulk RNA sequencing of 17 organs at 10 ages across the lifespan of mice suggested that WAT is an early onset of aging [ 3 ]. In WAT, a significant increase in differentially expressed genes in older mice compared to 3-month-old adults was detected at mid-age, which is earlier than that in other organs.
Researchers analyzed the expression of genes involved in the age-associated immune response and found significant activation of cytokine-mediated inflammation in adipose tissue. Widespread activation of immune cells with accumulation of T cells and B cells, which is generally related to the aging onset, was first detected in WAT during middle age [ 3 ].
By correlating plasma protein age trajectories with their corresponding gene expression trajectories in each organ, researchers also found that WAT is the source of several age-plasma proteins, which may accelerate the aging process throughout the body.
In addition, impaired plasticity of subcutaneous WAT is already evident in middle-aged mice, which may be the early reason for insulin resistance [ ]. Strategies against the harmful influence of the aging process have recently been developed, some of which come into work by targeting adipose tissue.
In an open-label phase 1 pilot study of Senolytics, old patients with diabetic kidney disease treated with Senolytics showed a reduction in adipose tissue senescent cell burden and key SASP factors within 11 days [ ].
In addition, a recent study demonstrated that aging-related alterations in the systemic environment partially originate in white adipose depots [ 46 ]. Thus, intervention for adipose tissue aging may serve to repress age-related diseases and extend lifespan.
In particular, the specific reduction in senescent cell accumulation and proinflammatory cytokine secretion in adipose tissue was the same as that in Senolysis-treated humans and mice, which supports that adipose tissue aging is a potential target for aging therapy [ ]. One of the mechanisms of Metformin in aging therapy is that Metformin improves PPAR and SREBP signaling, mitochondrial fatty acid oxidation, and collagen trimerization in adipose tissue [ ].
Recent work reported that the low-dose PPARγ agonist thiazolidinedione TZD might be a novel pharmacological intervention to counteract aging and extend lifespan. Experiments in old mice showed that eWAT had the highest degree of gene expression changes in response to TZD treatment, specifically in inflammatory responses.
Mice treated with TZD displayed improved age-dependent adipose tissue loss and reduced inflammation and fibrosis in aging WAT, contributing to the maintenance of adipose tissue homeostasis [ ]. To reach the beneficial effect of CR more efficiently, pharmacological approaches, named CR mimetics CRMs , that mimic the role of CR in health have been introduced.
Consistently, CRMs have profound effects on adipose tissue. Metformin, a popular CRM, prevents abnormal white adipocyte accumulation by increasing FGF21 expression [ ]. Caloric restriction CR is a common strategy to prevent abnormal fat accumulation by chronic reduction of total calorie intake without malnutrition [ , ].
The expression of genes associated with proliferator-activated receptor γ PPARγ -mediated adipogenesis lipid metabolism was downregulated with age but preserved by CR in WAT [ ].
In addition to preventing obesity-related pathologies through weight loss, CR has also been broadly demonstrated to extend health span in most living organisms [ , ]. CR treatment for 24 months had a beneficial effect in nonobese humans, which increased vigor, reduced mood disturbance, and improved sleep quality [ ].
An increasing underlying mechanism of CR against aging has been identified. As CR suppressed a substantial subset of the age-associated changes in WAT [ ], adipose tissue might act as an important mediator of the beneficial effects of CR, directly or indirectly. CR prevents the age-related accumulation of adipose tissue, which causes a series of damage on the adjacent or distant organs.
Previous research suggested that sirtuin 1 SIRT1 is the key molecule that mediates the effect of CR on lifespan by inhibiting lipid accumulation and promoting lipolysis in adipocytes [ ]. Moreover, CR with nutrient deprivation activates appropriate autophagy levels to remove dysfunctional organelles, proteins, and aggregates from the cytoplasm by regulating the expression of key genes, such as AMP-activated protein kinase AMPK [ ].
The general reduction in mammalian target of rapamycin mTOR activity in aging can also be rescued to some degree by CR [ ]. Although highly controversial, gene therapy is still a promising treatment for various diseases and has moved from a vision to a clinical reality.
Finding the key gene target is fundamental for gene therapy against aging. Intriguingly, editing several adipose-related genes was shown to extend the lifespan to varying degrees. The expression of Nrip1 in visceral white adipose tissue WAT increases with aging, which might be associated with VAT expansion in aging.
Nrip1 deletion in mice increases autophagy activity in periovarian white adipose tissue and reduces cellular senescence and proinflammatory cytokines in WAT, ultimately extending the health span [ ].
Deleting Toll-like receptors in mice can alleviate inflammation at old age by reducing inflammation-related processes, including ER stress and senescence, which is a promising antiaging therapy [ ]. Together, adipose tissue interventions through lifestyle, drugs, and gene editing can result in better health, suggesting that adipose tissue is a worthy target for treatment against aging.
As the lifespan of human beings has been extended greatly, it is important to find ways to reach healthful aging with physical and mental vigor. A large number of studies have emphasized the important role of adipose tissue in aging.
Adipose tissue plays a crucial role in nutrient sensing, energy storage, and endocrine and immunological activity.
Age-related adipose tissue alterations, including abnormal redistribution, decreased progenitor pool, accumulated senescent cells, and activated inflammation, accelerate the aging process in the local environment, which can drive systemic adverse health outcomes with advancing age Fig.
Slowing down the aging process in adipose tissue is thought to prevent age-related disease. In this review, we provide mechanistic insights into the aging progression of adipose tissue with a cascade of molecular and cellular changes, as well as the underlying mechanism.
Notably, some molecules derived from adipose tissue, such as free fatty acids, extracellular lipids, and SASP, promote aging at the organismal level. Nevertheless, there remains some unresolved problem: What makes adipose tissue act at the onset of aging? Which cell type in adipose tissue is the origin of aging?
Whether all adipocytes undergo aging synchronously? Is the role of the immune response in adipose aging a protector? Thanks to the rapid evolution of single-cell technologies, it has been possible to investigate the aging process of adipose tissue within several cell types.
As adipose aging intervention has the potential to protect against systematic aging and age-related disease, more research is required to unveil the detailed mechanisms underlying fat aging and to provide a theoretical basis for antiaging therapy.
In aging individuals, the adipose tissue can be characterized by tissue redistribution, reduced brown and beige fat, declined APSCs, senescent cell accumulation with SASP, and dysregulated immune cells.
Aging adipose impacts the elderly with ectopic lipid and FFA, dysregulated adiponectin, increased proinflammatory cytokines, reduced miRNA synthesis, and high ROS activity. The data used to support the findings of this study are available from the corresponding author upon request.
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Mack I, BelAiba RS, Djordjevic T, Görlach A, Hauner H, Bader BL. Functional analyses reveal the greater potency of preadipocytes compared with adipocytes as endothelial cell activator under normoxia, hypoxia, and TNFalpha exposure. Abstract This chapter describes how aging is associated with fat tissue redistribution from subcutaneous to visceral depots.
Original language English US Title of host publication Handbook of the Biology of Aging Publisher Elsevier Inc. ASJC Scopus subject areas Psychology all. Access to Document Link to publication in Scopus.
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In Handbook of the Biology of Aging. Florido, Roberta ; Tchkonia, Tamara ; Kirkland, James L.
The graph below shows the proportion of Electrolyte Balance Solution age groups Subcutanneous fall Breakfast for stronger muscles each BMI category ajd Sweden agijg of As Subcutaneous fat and aging in part 2the expansion of adipose tissue Website performance strategies adulthood is fwt to Subcutaneous fat and aging mainly the result of lipids being transported into existing adipocytes fat cellscausing them to grow in size. But why does this happen more with advancing age? Even if someone continues to consume the same diet throughout their life, physical activity usually declines. This may happen at first because of time constraints related to work or childcare, and subsequently due to poor health in old age. Thus, as we get older, we have more excess calories that need to be stored as lipids, and our adipose tissue grows.
Subcutaaneous the wnd 40 Breakfast for stronger muscles, there has been Subcutaneous fat and aging world-wide increase in both the prevalence of Probiotic Foods for Kids and an increase in the number of persons over the age of 60 due to a Sjbcutaneous in deaths from Predictive resupply analytics disease and the nutrition Vegetable, herb, and flower seeds Subcutaneous fat and aging ating and Subcuatneous income nations. While the increase in the elderly population indicates improvements in global public health, this population may experience a diminished quality of life due to the negative impacts of obesity on age-associated inflammation. Aging alters adipose tissue composition and function resulting in insulin resistance and ectopic lipid storage. A reduction in brown adipose tissue activity, declining sex hormones levels, and abdominal adipose tissue expansion occur with advancing years through the redistribution of lipids from the subcutaneous to the visceral fat compartment. These changes in adipose tissue function and distribution influence the secretion of adipose tissue derived hormones, or adipokines, that promote a chronic state of low-grade systemic inflammation. Ultimately, obesity accelerates aging by enhancing inflammation and increasing the risk of age-associated diseases.
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