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🛑 IS RETINOL KILLING YOUR FAT PADS And AGING YOU ??🛑 Face FatThe graph below shows the proportion of Subcutaneous fat and aging age groups that fall fah each BMI Subcytaneous in Sweden as of As fta in part 2the agng of Subcutaneohs tissue during adulthood is thought to be fay the result of Subfutaneous being transported into existing aving fat Sbucutaneouscausing them to grow in size.
But why does this happen more with advancing ans Even if someone continues Enhanced protection against harmful germs consume the same aginb throughout Subuctaneous life, physical activity usually agjng.
This abing happen Subcutabeous first because of aginng constraints related to work or childcare, and subsequently due to poor health in Subcutaneous fat and aging age. Thus, as we get older, Subcutandous have more excess calories that Subcutaneoys to be stored as lipids, and our adipose Weight management resources grows.
The second explanation is Subcutaneojs older adults have a lower resting metabolic Subcutaneoous — zging is to say, the Subcutaheous at which the body consumes calories when not engaging in physical activity Subcutxneous lower Subcutameous older age.
Some research suggests that resting adn rate remains Subcuyaneous stable until age 60, which would suggest that the first explanation is the anc cause of weight gain Subcutaneohs middle age. With increasing age, SSubcutaneous tend to be redistributed away from SAT in favour of VAT. More tat also get stored outside the adipose tissue, such as within liver Subcutaneous fat and aging Injury prevention through proper nourishment cells, fah is agiing bad thing because this promotes insulin an again, see part 3 for a recap.
Additionally, the amount Natural Appetite Suppressant brown Subcutaneoous tissue responsible for generating heat and beige adipose tissue a type Subcutaneos tissue somewhere snd white and brown decreases during ageing.
Changes Subutaneous molecular aginh with age such as xnd changes and increased inflammation are likely to play a role in the reduction of SAT in favour of VAT. Subcutaneous fat and aging the most obvious fah of this Subcutaneous fat and aging that Suubcutaneous tend to gain visceral fat following the menopause.
Adipocyte amd cells — fta cells responsible for generating new adipocytes — also die off during ageing. This Subcutaneoks adipose Subcuatneous less able to adapt and accommodate Subcitaneous lipids fay forming new adipocytes, which could lead to Subcutaneous fat and aging lipids being stored Subcutaneous fat and aging other Subcutaneous fat and aging like liver and muscle.
Until this point, we have talked about adipocytes as Isotonic drink for sports firmly into one category or another: white or brown, faf or visceral.
However, adipocytes agng some flexibility in their function. This means they will amd their lipid stores more readily than they would in a fed state, while restricting their Subcutneous consumption tat fatty acids when All-natural digestive aid heat.
This is a good thing: it means that adipose tissue can adapt to the aying of the body, soaking up excess calories in times of Subcytaneous, and rat them Subchtaneous necessary.
When an older person snd a Subcutaneous fat and aging of agung, their adipocytes are less able to shut down the release of lipids and to accommodate the anv influx Subcutaneous fat and aging nutrients. This may be caused in part by changes in Cognitive health strategies signalling see belowand may also be related to the increased size of the adipocytes in older people.
As seen in part 2adipose tissue is more than a mere storage system. Through the signalling molecules it releases, adipose tissue plays an important role in regulating how the metabolism handles energy.
One of the ways it does this is by suppressing appetite through the release of hormones like leptin. With increasing age, this signalling system starts to malfunction as adipocytes die or become senescent a state in which they stop dividing and release inflammatory molecules.
These changes makes adipocytes less able to take up glucose from the blood, and more prone to release their lipid stores as fatty acids, which then build up in other tissues. While the effects of ageing on adipose tissue are well established, there is also mounting evidence that a reverse relationship exists: having too much white adipose tissue can accelerate ageing and promote age-related diseases.
How this happens is an ongoing area of research — after all, we are still a long way from fully understanding how humans age to begin with. Scientists have identified prominent mechanisms by which white adipose tissue might contribute to ageing.
This leads to insulin resistance, sustained high blood sugar and eventually type II diabetes see part 2 for a recap. This matters in ageing because type II diabetes and insulin resistance in general appear to promote the development of all age-related diseases.
The ways in which insulin resistance contributes to ageing are complicated and various. When tissues stop responding to insulin, insulin-producing cells in the pancreas respond by increasing their insulin production.
These systems regulate processes thought to be protective against ageing like the repair of DNAand these protective effects are inhibited by insulin. This glucose can bind to proteins or lipids in the blood to form molecules called advanced glycation end-products AGEs.
These molecules can stick other proteins together, preventing them from working and contributing to the progression of age-related diseases. The mitochondria are the power plants of the cell. They convert nutrients from our food into the universal cellular fuel, a molecule called ATP.
In obesity, the mitochondria become overloaded by a surplus of nutrients. This damages the mitochondria, reducing their efficiency over time, and generates harmful molecules called reactive oxygen species, which can damage other molecules including DNA. These changes may contribute to accelerating the ageing process in people with obesity — for more information about how mitochondrial dysfunction contributes to ageing, see this article.
As seen in part II, white adipose tissue generates inflammatory molecules, and in obesity, white adipose tissue becomes increasingly inflammatory, while insulin resistance and mitochondrial dysfunction also promote the production of inflammatory molecules.
Some of these molecules find their way into the bloodstream to promote inflammation throughout the body — this is called systemic inflammation or background inflammation. A sustained increase in inflammatory molecules is bad because inflammation is involved in driving pretty much every age-related disease.
See this article for more information about the link between inflammation and ageing. While cells other than adipocytes are capable of storing some lipids, they are not specialised for the task, and quantities of lipids that adipocytes could accommodate easily quickly become toxic for non-adipocytes.
This is known as lipotoxicity, and it results in disease and death of affected cells, which damages affected organs, most commonly the kidneys, liver, heart and skeletal muscle.
With that, our 4 part series on adipose tissue comes to a close. We have seen how fat, whether it refers to lipids or to adipose tissue, is often misunderstood. We need to consume lipids in order to remain healthy, and we need adipose tissue to buffer the calories we consume, to regulate our appetite and energy expenditure, to keep us warm and much more.
Unfortunately, when adipose tissue stops working properly in obesity or ageing, the consequences can be severe. The intention of this series was not to provide health advice, but rather to help you understand how adipose tissue works and how it interacts with the ageing process.
Many scientists are also interested in working out the molecular mechanisms behind the benefits of calorie restriction, and targeting them using drugs. We have reported on some of this research in the past, and will of course continue to do so for future developments.
Until then, look after your adipose tissue, and it will look after you! Sign up for our newletter and get the latest breakthroughs direct to your inbox. At Gowing Life we analyze the latest breakthroughs in aging and longevity, with the sole aim to help you make the best decisions to maximise your healthy lifespan.
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Part 4: Ageing And Fat Posted on 5 May With age, white adipose tissue WAT expands, while brown adipose tissue BAT is reduced. Ectopic fat ECT, fat stored in locations other than adipose tissue increases. Insulin resistance drives or is implicated in a diverse range of diseases.
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: Subcutaneous fat and aging| Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis | o Re-clustering of IC1-IC3 in a , b identified 8 specific immune cell subpopulations, samples from 3 young individuals and 3 old individuals. p Dot plot shows the expression levels of representative cell-type-specific marker genes across all these 8 immune cell subpopulations. q Interaction heatmap plots the total number of cell receptor y axis and ligand x axis interactions in 3 young donors left and 3 old donors right derived SAT. The color key from blue to red indicates low to high number of interactions. s — u Primary human APC treated with conditioned media from DOX-induced senescent macrophages. s Representative images of SA-β-gal staining of conditioned media treated APC. of 3 fields. t Representative images of Oil Red staining show the adipocyte differentiation of conditioned media treated APC. of 3 biological replications. u Representative images of immunofluorescence staining of Ki67 in conditioned media treated APC. In dot plot d , j , p , the size of the dot corresponds to the percentage of cells expressing the specific gene in each cluster, and the color encodes the scaled average expression level of feature genes across all cells within a subpopulation. Interestingly, it was noted that the cell number of inflammatory APC5 increased significantly with aging Fig. Analysis of aging-dependent differentially expressed genes showed that the expression level of cell surface markers PLAU and THBD were significantly increased in aged APC5 Fig. Immunofluorescence staining and flow cytometry of human adipose tissues based on PLAU and THBD verified the accumulation of APC5 in old individuals Fig. These findings indicated that human SAT contain a subset of defective inflammatory APC population that accumulates with aging. In scRNA-seq analysis on SAT from another independent cohort of young and aged donors, we also identified inflammatory APC populations APC3 and APC4 that accumulate with age and exhibit higher levels of PLAU and THBD expression, further supporting the notion. supplementary Fig. S3 , Fig. As one of the biomarkers of APC5, PLAU was also predicted as a frailty marker in previous study. Thus, we speculated that PLAU might be involved in the progression of APC aging. To test this hypothesis, we firstly measured the expression level of PLAU in human primary APC derived from young year-old and old year-old individuals. The qRT-PCR results showed that PLAU expression level was positively correlated with donor age supplementary Fig. Additionally, the adipogenic differentiation capacity of APC from elderly individuals was significantly lower than that of young individuals supplementary Fig. Senescence-associated β-galactosidase SA-β-gal staining showed that overexpression of PLAU overexpressing efficiency, S5c, d. Next, we investigated whether down-regulation of PLAU could rescue APC aging. Knockdown of PLAU silencing efficiency, Collectively, these results suggested that aberrant expression of PLAU promotes APC aging, and may represent a promising therapeutic target for aging related diseases of human adipose tissues. Previous studies showed that adipose tissue functions are tightly regulated by the crosstalk between APC and immune cells. Re-clustering of IC1-IC3 cells identified 8 specific immune cell subpopulations ICS ICS1, ICS3, ICS6 showed gene expression signatures of distinct T cell subpopulations Fig. While ICS6 expressed higher levels of the early T cell activation markers CD69 and CXCR4 , ICS1 was distinguished from ICS6 by high expression levels of ribosomal protein-related genes, representing a proliferating cell population supplementary Table S5. ICS5 was identified as M2-like macrophage by the expression of CD , and ICS7 was recognized as M1-like macrophage for high expression level of FCGR3A Fig. After cell type annotation, we utilized CellPhoneDB and iTALK to perform unbiased ligand-receptor interaction analysis between the ICS and APC. Both algorithms demonstrated that M1-like macrophage ICS7 maintained a relatively strong interaction with other cell subpopulations Fig. Particularly, iTALK analysis showed that aging shifts the intercellular chemokine crosstalk from an APC-dominating pattern to an M1-like macrophage-dominating pattern Fig. To study whether the macrophage-dominating interaction pattern contributes to APC dysfunction, we cultured human primary APC derived from young individuals with conditioned medium of Doxorubicin DOX -induced senescent M1 macrophages supplementary Fig. S6a, b. Conditioned medium of senescent macrophages significantly increased PLAU expression level in young human primary APC supplementary Fig. Moreover, conditioned medium treatment promoted senescence of human primary APC Fig. S7a, b. Results also showed that M1 macrophages of aged SAT significantly elevated the inflammation genes expression of APC supplementary Fig. Overall, our findings demonstrated that senescent macrophages play a critical role in promoting APC aging. The raw sequencing data have been deposited to Genome Sequencing Archive of the National Genomics Data Center accession: HRA All other data and materials used in this work are available from the lead corresponding author hwoy zju. cn upon request. Zwick, R. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. Article CAS PubMed PubMed Central Google Scholar. Nguyen, H. et al. Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis. Cell 56 , — e Cardoso, A. Towards frailty biomarkers: candidates from genes and pathways regulated in aging and age-related diseases. Ageing Res Rev. Article CAS PubMed Google Scholar. Hildreth, A. Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity. Spallanzani, R. Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors. Download references. This work was supported by the National Natural Sciences Foundation of China T, We would like to thank The Core Facilities of Zhejiang University-University of Edinburgh Institute for technical assistance. Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, , China. Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, , China. Wenyan Zhou, Junxin Lin, Yuemin Ou, Hongwei Wu, Yiyang Yan, Aaron Trent Irving, James Q. Department of Plastic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, , China. The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, , China. Department of Orthopedics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, , China. China Orthopedic Regenerative Medicine Group CORMed , Hangzhou, , China. You can also search for this author in PubMed Google Scholar. Conceptualization by H. Lou; Methodology by W. Lin, and H. and J. Lin; Review and Editing, Y. Correspondence to Hongwei Ouyang. Human adipose tissues were obtained from patients undergoing specific surgical procedure with the approval of the ethics committee of Second Affiliated Hospital, Zhejiang University Approval number: and General Hospital of Ningxia Medical University Approval number: KYLL Open Access This article is licensed under a Creative Commons Attribution 4. total views article views downloads topic views. With their unique mixes of varied contributions from Original Research to Review Articles, Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author. Overview Articles Authors Impact. About this Research Topic Submission closed. With old age, fat distribution shifts from subcutaneous to visceral fat depots, while triglycerides ectopically deposit on liver, muscle, bone marrow, and heart. These changes are associated to the development and progression of a variety of age-associated diseases. Human aging is characterized by a chronic, low-grade inflammation that develops in various aging tissues. Among the major source of inflammaging immunosenescence, self-debris, senescent cells, mitochondria dysfunction, microbiome, and adipose tissue can be included. Similar to inflammaging, obesity is linked to a systemic, chronic, low-grade inflammation. Whether inflammaging and metaflammation share common inflammatory pathways or have similar sources of inflammation, including the role of different fat depots, are important questions. It is likely there are fundamental differences between diet- versus age-dependent obesity, given the widespread immunological and physiological changes that are known to occur in old age. |
| Top bar navigation | Comparisons of subcutaneous versus visceral adipose progenitors have been done in model organisms; however, more research is needed to determine whether differences between depots in humans can explain the redistribution of adipose tissue in human aging. Cellular changes in adipose and skeletal muscle with aging. Immune cell infiltration increases with age, and accumulation of aging-dependent regulatory cells is seen. In skeletal muscle, mitochondrial function is decreased with aging, satellite cells lose ability to maintain quiescence, and myocytes undergo atrophy. Recently, a novel subpopulation of cells named aging-dependent regulatory cells ARCs was identified through single-cell RNA-Seq analysis of subcutaneous adipose tissue ARCs are proinflammatory and inhibit differentiation and proliferation of neighboring progenitor cells, but are distinct from senescent cells in that they can proliferate. Interestingly, these cells were found only in subcutaneous, and not in visceral, adipose tissue in mice. It is not yet known whether they exist in visceral adipose tissue in humans. Nguyen et al. Adipose tissue is composed of not only adipocytes and adipocyte progenitor cells, but a complex milieu of immune cells including but not limited to NK cells, T cells, eosinophils, and macrophages. Proinflammatory immune cells accumulate in adipose tissue with aging and have been linked to development of systemic chronic low-grade inflammation. There are limited data in humans regarding the effects of aging on adipose immune cell composition and function. Eosinophil abundance in human adipose tissue appears to have a negative correlation with age, and studies in mice indicate that eosinophils may play a role in mitigating age-related adipose tissue inflammation Adipose tissue macrophage abundance correlates with adiposity as well as adipocyte size and therefore may be expected to increase with aging. However, many studies describing this association were conducted in the context of obesity, and therefore the impact of aging alone is unknown 55 , Adipose tissue plays a major role in endocrine signaling via secretion of adipokines. One such adipokine, adiponectin, which is associated with lower risk of metabolic syndrome in older adults 57 , 58 , is increased in centenarians and their children compared with non-centenarians Data from animal models suggest that maintenance of adiponectin levels promotes metabolic health and prolongs life span However, some studies in humans have shown a relationship between higher adiponectin levels and sarcopenia, frailty, and even mortality 61 — There is some speculation that higher levels of adiponectin may be secondary to compensatory mechanisms in response to inflammation and oxidative stress, or may be related to adiponectin resistance, but further study is needed to clarify these points. Skeletal muscle is an important tissue for glucose and fatty acid metabolism, as well as a major site of body protein. This difference is even more evident when imaging techniques such as CT or MRI are used. Cross-sectional comparisons between young and older study participants suggest that by age 60 humans will lose approximately 0. Thus, muscle loss includes both locomotive and postural muscles. Together with loss of muscle mass, there is often an increase in intramuscular adipose tissue 68 — so-called marbling. This is to be distinguished from intramyocellular lipids, which have also been reported to be increased with aging 10 , 70 , Intramuscular adipose tissue is a marker of, but unlikely to be a major cause of, muscle dysfunction. This is because intramuscular adipocytes, when present, are adjacent to blood vessels outside the perimysium; that is, there are no adipocytes inside muscle fascicles Because there is no portal system in skeletal muscle, intramuscular adipocytes are unable to provide fatty acids or lipokines to myocytes directly. The lesser amount of skeletal muscle in older adults is accompanied by reduced muscle function. There are progressive declines in peak VO 2 ref. The loss of strength 2. An autopsy study indicated that muscle atrophy begins around 25 years of age and thereafter accelerates owing to a loss of fibers more than to a reduction in fiber size 76 , although others have suggested that reduced fiber size is a more important determinant of muscle atrophy The loss of muscle has implications for both mobility and metabolic regulation muscle is the primary site of insulin-mediated glucose storage and oxidation , making the physiological explanation for age-related muscle loss an important area of study. Muscle proteins are constantly turning over; older, damaged proteins are replaced by newly synthesized proteins. Normally, muscle protein synthesis anabolism is stimulated by meal consumption and resistance exercise The amino acids, especially leucine, provided by meal consumption are thought to be the main drivers of this anabolic response. The combination of resistance exercise and meal protein consumption is synergistic with respect to muscle protein synthesis Insulin acts to restrain muscle protein breakdown, even in the fasting state Aging has been shown to be associated with resistance to the anabolic effects of both resistance exercise and meal consumption, as well as resistance to the anticatabolic effects of insulin A substantial portion of the loss of muscle mass and strength with aging is due to reduced physical activity. Adults who maintain high levels of physical activity into their 60s and above have less body fat and more muscle, are more fit, and are stronger 28 , 70 , That said, even those who maintain such high levels of physical activity suffer declines in fitness and strength over time, indicating a primary aging effect. Do these primary effects of aging account for the observed insulin resistance with respect to glucose metabolism that has been described in older adults 80? Although insulin resistance with respect to glucose metabolism was once thought to be primarily an effect of aging, it is now known that the greater amounts of body fat 81 and particularly visceral fat 82 are much better predictors of insulin resistance than is age. In fact, after accounting for body fat and fat distribution, age and fitness do not predict insulin action with respect to glucose metabolism There may also be abnormalities of muscle lipid metabolism associated uniquely with aging, although not as many studies have been done. In response to leg exercise, leg muscle of older men utilizes more plasma FFA and less intramuscular triglycerides than that of young men The intramyocellular content of ceramides and diacylglycerols, especially of the saturated fatty acid varieties, is greater in older than in younger men Plasma FFA concentrations correlate with intramyocellular lipid content in some thigh muscles; intramyocellular lipid content inversely correlated with measures of strength in young, but not in older, adults In summary, much of the insulin resistance with respect to glucose metabolism that was attributed to aging is, in fact, more strongly related to the tendency for older adults to develop central obesity. Maintaining a healthy amount of body fat with aging reduces the risk of central obesity—related metabolic disorders, and maintaining high levels of physical activity including resistance exercise can partially offset the progressive loss of muscle mass. Activation of muscle progenitor cells, or satellite cells, is necessary for muscle regeneration, given that myofibers are terminally differentiated. Satellite cells exist in a quiescent state between the sarcolemma and basal lamina in muscle. When activated in response to damage or stress, satellite cells proliferate and eventually fuse, forming new myofibers. A subset of cells reenter the quiescent state, thereby maintaining the progenitor cell pool. In vitro analysis of satellite cells obtained from human muscle indicates that with aging of the individual, satellite cells maintain their capacity to proliferate and differentiate However, immunohistochemical analysis of muscle biopsies indicates that the number of satellite cells per muscle fiber decreases with age Aged human satellite cells also have reduced ability to remain quiescent and exhibit features of cellular senescence including p16 INK4a expression 87 , which may contribute to depletion of the progenitor cell pool over the life span. In addition to cell-intrinsic factors, age-related changes in the progenitor cell niche, including the extracellular matrix, may also affect the ability to maintain quiescence 88 , 89 Figure 2. Mitochondrial function, including ATP synthesis and oxidative capacity, decline with aging in skeletal muscle It is not entirely clear whether these changes are related to primary aging or are secondary to decreased physical activity 91 , 92 ; however, recent evidence suggests that both factors contribute 18 , likely to varying degrees between individuals owing to heterogeneity along the life span. Mitochondrial DNA mtDNA accumulates mutations with aging, and mtDNA copy numbers, which are associated with oxidative capacity, do seem to decrease with aging independent of changes in activity These changes may lead to reduced synthesis of mitochondrial proteins, in turn impacting metabolic capacity. A number of pathways have been implicated in the muscle atrophy of aging using rodent models. These include activation of activating transcription factor 4 ATF4 , which, through a complex pathway 94 , appears necessary for muscle atrophy to occur with aging mice that lack ATF4 in skeletal muscle fibers maintain muscle strength and mass into old age; ref. Although how the liver changes with age in humans has not been studied as much as how skeletal muscle and adipose tissue change, the central importance of the liver in metabolic function is such that what is known must be considered. It has also been reported that older adults are more likely to have increased liver fat and that greater amounts of liver fat are associated with metabolic abnormalities However, the greater amounts of liver fat in older adults may well be explained by their greater tendency to have increased total body and visceral fat. Most of the differences between younger and older adults with respect to hepatic glucose metabolism can be accounted for by differences in body fat and body fat distribution 82 , although increased hepatic insulin clearance combined with decreased peripheral insulin clearance appears to be linked with aging more than body composition or fitness 82 , Thus, the evidence suggests that the role of the liver in modulating how insulin secretion results in peripheral insulin delivery is directly modulated by aging. Some of the other factors that may contribute to abnormalities in hepatic metabolism with aging are hormonal changes. In addition to the changes in sex steroids outlined above, aging is associated with delayed and impaired insulin secretion 35 , 98 , greater fasting plasma cholecystokinin CCK and glucagon-like peptide-1 GLP-1 concentrations, and greater CCK and GLP-1 responses to protein ingestion Thus, untangling the roles of hormonal changes that accompany aging from age-specific differences in liver function in humans is not easy. Caloric restriction CR , the reduction of calorie intake without malnutrition, has been shown to increase life span and improve metabolic health in multiple model systems. A study of CR in humans the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy [CALERIE] showed weight loss, reduction in total daily energy expenditure, and reduction of the inflammatory markers TNF-α and CRP A follow-up study showed reduction of subcutaneous and visceral abdominal adipose tissue mass as well as less intramyocellular lipid content after calorie restriction Given the beneficial effects of CR, but the considerable effort required to achieve this intervention in the short and especially the long term, much investigation has been conducted into pharmacologic interventions to mimic CR reviewed by Madeo et al. One of these interventions has been resveratrol. Randomized trials of resveratrol have documented changes in muscle mitochondrial function and adipose gene expression , but no clinically meaningful responses. As noted above, older adults who exercise regularly have less central body fat, better muscle function, and better insulin sensitivity than sedentary older adults 45 , 66 , 70 , 79 , and exercise training, with or without weight loss, improves muscle mass and function in older adults 26 , Satellite cell content and activation increase in response to exercise — , and data from animal studies are beginning to elucidate the mechanisms by which exercise may improve progenitor cell function Metabolic abnormalities with aging seem to be most readily addressed by aggressive resistance training, which can offset some, but not all, of the anabolic resistance in muscle Thus, of the interventions that have been studied, exercise training appears to have the most wide-ranging benefits when it comes to muscle and adipose tissue health, the latter at least partly through prevention of excess fat gain. The beneficial effects of resistance exercise on skeletal muscle mass and strength are enhanced by provision of adequate protein intake Increased protein intake is needed for older adults to achieve a response to exercise training similar to that of their younger counterparts, owing to anabolic resistance Leucine supplementation and β-hydroxy-β-methylbutyrate HMB supplementation may be beneficial for increasing muscle mass in older adults with sarcopenia independent of exercise Other nutritional approaches to enhance muscle mass and function with aging include supplementation with omega-3 fatty acids , , although it is unclear through what mechanism this benefit occurs. Several pharmacologic approaches to improve muscle function with aging have been tried; the outcomes of the resveratrol trials were mentioned above. Pioglitazone, given in combination with a weight loss program with or without resistance exercise, results in greater loss of visceral fat in older men , and perhaps greater strength gains when combined with resistant training in older women Many preclinical investigations are ongoing to identify mechanisms of age-related muscle atrophy and dysfunction and to test novel therapeutics targeting newly discovered pathways. For example, therapeutics that target the atrophy mechanisms downstream from ATF4 have included ursolic acid and tomatidine, which promote skeletal muscle hypertrophy 95 and appear to increase mTORC1 activity in skeletal muscle. However, translation to successful clinical applications has so far been limited Senescent cells have emerged as an attractive therapeutic target in the prevention and treatment of age-related and metabolic disease A recent study in humans with diabetic kidney disease demonstrated the ability of senescent cell—targeting, or senolytic, drugs to remove senescent cells from human adipose tissue Further study is needed to determine whether senescence-targeting therapies can improve body composition and metabolic health in aging humans. Aging is associated with increased adiposity, and the prevalence of obesity is increasing in the older adult population. However, the tendency toward loss of peripheral adipose tissue and the muscle atrophy that accompanies aging cannot be completely prevented. Adequate dietary protein, perhaps omega-3 fatty acids, and exercise training are the current mainstays of preventing metabolic abnormalities with aging. Correcting pathological hormonal deficiencies can also result in positive metabolic changes. Therapeutics that mitigate the effects of senescent cell accumulation or target stem cell populations in adipose tissue and atrophy pathways in muscle are on the horizon. These could combine to further improve the metabolic health of older adults. This work was supported by NIH grants, DK and DK The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Conflict of interest: AKP is a listed inventor on patents on senolytic drugs held by Mayo Clinic, USA1 and USA1. Copyright: © , Palmer et al. This is an open access article published under the terms of the Creative Commons Attribution 4. Reference information: J Clin Invest. Go to JCI Insight. This is the reason for the spatially heterogeneous structure of dWAT, even in the same body area [ 32 ]. The results reported demonstrate the periodic evolution of dWAT: dWAT is present in 6-week-old mice anagen phase of HFs , depleted in 9-week-old mice telogen phase , significantly increased in week-old mice anagen phase over its value in 6-week-old animals, reduced in week-old mice telogen phase and then strongly increased in adult week-old mice. Interestingly, this dWAT evolution is significantly correlated with skin stiffness, thereby demonstrating the inverse dependence of dWAT on skin thickness, being the lowest in week-old mice. At the same time, age-dependent modifications of dWAT can easily be observed in different knock-out mouse models demonstrating accelerated aging phenotypes. Another model which is useful in chronological aging studies is the PASG proliferation associated SNFlike gene null mouse, which also displays distinct signs of premature aging. In addition, p53 mutant mice displaying an early aging-associated phenotype demonstrate depleted dWAT structures in month-old animals which can be considered as very old , whereas the wild type mice of the same age show significantly reduced but still present dWAT layers [ 36 ]. Recapitulating, the chronological evolution of dWAT in intact mice seems to be associated with a periodic modulation of the volume of this depot till mid-age and its subsequent continuous strong involution in old animals. UVR can significantly modulate sWAT metabolism. This effect is observable not only in chronically sun-damaged human skin, but even after a single UV exposure of a non-damaged skin [ 37 ]. These authors have shown that the free fatty acid and triglyceride content in sWAT of sun-exposed skin forearm is significantly lower than in the buttocks sun-protected area of the same subjects. At the same time, young subjects did not demonstrate such differences, which points to the UV-induced effect and not just to the regional variations in fat metabolism. Additionally, both chronic and single UVR exposure significantly reduces master adipogenic factors such as peroxisome proliferator-activated receptor γ PPARγ ; this reduction was rapid and remained stable for at least 72 h after acute UVR exposure. To explain these results, the authors assumed that some soluble factors such as IL-6, IL-8, MCP-3 and PIGF produced in upper dermis during UV exposure diffuse into the sWAT and trigger modification of sWAT metabolism. This idea was supported by the fact that the treatment of mature adipocytes from sWAT with these cytokines provides a reduction of triglyceride content. The list of cytokines which could be involved in signal transduction from the skin to the sWAT was further extended in [ 38 ], where it was shown that the exposure of preadipocytes to conditioned medium from solar irradiated epidermal-dermal equivalents, containing such inflammatory cytokines as IL-1α, IL-6, IL and TNF-α, inhibited the differentiation of these cells into mature adipocytes. At the same time, application of antibodies neutralizing these cytokines was able to reduce the failure to differentiate significantly. This lead to the conclusion, that inflammatory cytokines are involved in the loss of sWAT during extrinsic aging. A single low-dose 1. This reduction correlated with the observed decreased levels of PPARγ in ovarial adipose tissue. Since the level of serum amyloid A in this study was shown to be significantly increased, the effect of UVB on remote adipose tissue depots was explained through endocrine responses mediated by amyloid A. However, since human dWAT structures can spatially reach the upper dermis Fig. If this model is correct, the rate of extrinsic aging in humans should demonstrate spatial correlations with dWAT structures. Analyzing the effects of UVR, these areas must additionally be separated into the sun-exposed and non-exposed areas. Body areas without dermal adipocytes are the palm and scalp [ 16 ]. From this point of view dWAT content correlates with a much more pronounced extrinsic aging process in the dorsal hand comparing to the palm area. Chronological skin aging demonstrates similar but not as pronounced differences in aging processes in palmar and dorsal regions of the hand. This can be an indication that UVR accelerates the processes of skin aging, whereas their basic components are determined by some other factors, one of which could be the local dWAT content. This can make skin aging not only body area dependent, but also spatially heterogeneous in the same body area, since dWAT can have a spatially heterogeneous structure [ 32 ]. Irradiation of human adipose-derived stem cells ADSCs with UVA in vitro demonstrated suppression of adipogenic differentiation potential of these cells. Such suppression could be observed already by very low fluence of 0. This effect was connected with an observed significant down-regulation of PPARγ expression caused by UVA and demonstrated strong dose- dependent effects. Accumulation of triglycerides in UVA-irradiated cells in this study was also significantly reduced in a dose-dependent manner. Taking into account that UVA of such low fluence as 0. These results demonstrate that adipocytes can react even to low doses of UVR with a suppression of PPARγ expression and adipogenic differentiation as well as with a reduced accumulation of triglycerides in mature adipocytes. This additionally supports the idea that not only systemic pathways, but also direct local responses in dWAT, can be involved in the reaction of sWAT to UVR in vivo , as observed in [ 37 ]. Chronic five times weekly, 20 weeks, However, this irradiation caused the disappearance of dermal adipocytes, the production of fibrosis and a significant increase of hyaluronan content in the lower dermis compared to control animals. Since it was possible to prevent the appearance of cutaneous fibrosis by hydrocortisone, it was concluded that such modifications of the skin structure were caused by an inflammatory reaction induced by UVR. Whereas no significant anatomical changes were observed after weeks of irradiation, a substantial reduction of dWAT and increased accumulation of collagen fibers were observed after 8 weeks of UVR. At the same time, the dermal thickness in 8 week-old UVA-irradiated mice was not statistically different from corresponding age controls which points at the replacement of dWAT layer with cutaneous fibrosis. These earlier results must be re-analyzed, taking into account the recently discovered property of dermal adipocytes to undergo transition into the mesenchymal cells AMT [ 25 ]. This transformation was recognized to be an important pathophysiological step in cutaneous fibrosis. AMT in [ 25 ] was induced by subcutaneous injections of bleomycin. AMT has universal features seen under many circumstances, and can be induced by different physical and chemical factors, among them also UVR. From this point of view, the results obtained in [ 43 , 44 ] can be interpreted as AMT caused by UV exposure Fig. This effect can be assumed not to be as pronounced as after bleomycin injection. Furthermore, the dWAT cellularity at the time of UVR application should be sufficiently high. This correlates with observations that the replacement of dWAT with cutaneous fibrosis after UVR was observed after sufficiently long UVR exposures as the mice reached the stage of adulthood, which associated with an expanded dWAT depot [ 31 ]. Figure 2. Possible role of adipocyte-myofibroblast transition in extrinsic aging. Absorption of UV radiation in the skin causes acute enlargement of the dWAT layer. However, upon chronic overexposure to UV radiation, it causes the depletion of dWAT and a concurrent development of cutaneous fibrosis, presumably through adipocyte-myofibroblast transition AMT. Replacement of dWAT volume with fibrosis leads to production of mechanically heterogeneous skin structures and to the loss of the effective skin volume. Replacement of dWAT with fibrosis through AMT should lead to the production of spatially heterogeneous skin structures. Additionally, this process should prompt the loss of effective skin volume, taking into account the total volume of dermis and dWAT, corresponding to the skin modifications observed in extrinsic aging. If correct, this effect can, at least in extrinsic aging, shift the point of interest from connective tissue to dWAT. We cannot fully exclude that the AMT mechanism is also somehow involved in the intrinsic aging. Skin reactions to UVR are not only dependent on the type and the dose of irradiation, but also on the content of the skin surface lipids among them prominently α-tocopherol. These lipids are commonly referred to as photo-protectants [ 48 ]. The content of these lipids in the skin is significantly reduced after a single UVR application. This can lead to a stronger UV absorption in the skin during a next round of UVR and thus accelerate skin aging. These lipids are believed to be mainly produced and secreted by sebaceous glands which were recognized as the major physiological source for their delivery to the skin surface [ 49 ]. Moreover, it is known that α-tocopherol can stimulate the expression of PPARγ and along with that lipid accumulation during adipogenic differentiation [ 51 ]. This PPARγ stimulation seems to be realized indirectly through inhibition of its antagonists [ 52 ]. Moreover, α-tocopherol can induce the expression of adiponectin, which is in line with its adipogenic effects [ 53 ]. These results provide an additional link to dWAT involvement in the skin reaction to UVR. Adipose tissue displays the slowest turnover for its stored α-tocopherol with an average half-life of days [ 54 ]. It is not known whether UVR can speed up the release of α-tocopherol from adipocytes located in dWAT. We would however predict that such an enhanced turnover rate should indeed occur, especially in the case of repeated UVRs that continuously deplete the α-tocopherol pool in the skin and thus force an additional outflow of this lipid from the adipocytes located near the skin surface. Hence, chronic UVR should deplete the pool of α-tocopherol in dermal adipocytes and thus also suppress the adipogenic differentiation potential and triglyceride accumulation in these cells. This would provide an explanation for the observed continuous reduction of dWAT in the skin chronically irradiated with UV. In contrast, a single UVR may induce a compensatory expansion of dWAT to provide a short-term pool of skin lipids. The reaction of dWAT to UVR should therefore be strongly dependent on the irradiation schedule. One of the most intriguing phenomena in skin aging is the acceleration of this process through application of different drugs. This effect is known, for example, for immuno-modulators such as cyclosporine A CsA. Whereas chronic exposure of the Skh-1 hairless mice to non-erythemal doses of UVB induced skin wrinkles after weeks of irradiation, concomitant systemic application of CsA reduced the onset time of wrinkling down to 4 weeks [ 55 ]. These results should be re-analyzed taking into account that the dWAT structure and activity in murine skin is dependent on the genetic strain and on the stage of the HF cycle [ 19 ]. A mutation of hr gene leading to skin baldness causes a disruption of the integrity of HFs as well as the production of utriculi open comedones and cysts in the lower dermis and subcutis [ 56 , 57 ]. CsA belongs to the group of immuno-suppressors which alter the production of cytokines and influence adipogenesis. This drug can specifically inhibit calcineurin, which is upstream of the nuclear factor of activated T cells NFAT transcription factor [ 61 — 63 ]. If NFAT takes part in premature skin aging as observed in [ 55 ], dWAT can also be affected, since this pathway is involved in the differentiation of preadipocytes as well [ 64 , 65 ]. Indeed, chronic application of some immuno-suppressors can reduce both adipocyte size and number [ 66 ] and it was proposed that CsA inhibits adipogenic differentiation through prevention of the nuclear localization of NFAT [ 64 ]. Hairless mice with thymus atrophy have a marked deficiency in functional T cells, including iNKTs which represent the resident population in adipose tissue [ 67 ]. Whereas it is actually not known which level of NFAT expression is typical for dermal adipocytes in athymic nude mice, we assume its expression is altered compared to wild-type animals. This can lead to impaired adipogenic differentiation in the dermis of these animals. This may be one of the reasons for the qualitative differences in effects of CsA on skin aging in different genetic strains observed in [ 55 ]. Murine dWAT demonstrates pronounced sexual dimorphism: females have dWAT layers which can be an order of magnitude thicker than in males, whereas the total skin thickness is higher in intact males [ 30 ]. After gonadectomy, the dWAT thickness significantly increases both in males and females, whereas treatment of these animals with dihydrotestosterone, 17β-estradiol or dehydroepiandrosterone markedly depletes this depot. Such effects were connected with ability of androgens to inhibit the adipogenic differentiation of stem cells and preadipocytes [ 68 , 69 ]. A sexually dimorphic response is also known for the response of mice to UVR: males demonstrate a reduced responsiveness to UVA radiation compared to females [ 70 ]. Such a response correlates with the lower thickness of dWAT in non-irradiated males and with the ability of UVA to reach the panniculus carnosus to affect dermal adipocytes. This again points to the involvement of dermal adipocytes minimally in the context of extrinsic skin aging. Whereas the sexual dimorphism of dWAT in humans was not clearly demonstrated, its gender difference is likely to be present in humans as well. This effect can at least partly explain the difference in the skin aging processes in male and female subjects [ 71 ] and will need further intensive investigation. Production of reactive oxygen species ROS is one of the primary responses in the skin reaction to UVR [ 72 , 73 ]. Despite the fact that ROS are often considered to be generally harmful, they in fact able both to stimulate and to suppress the cellular processes, such as the proliferation and differentiation of adipose tissue-derived stem cells ADSCs [ 74 ]. For example, whereas a high-dose UVB is able to suppress the proliferation of ADSCs, low-dose UVB can increase survival of these cells and up-regulate the expression of different growth factors [ 75 ]. Consequently, dWAT and sWAT should react to UVR in a dose-dependent and bi-phasic manner. The dWAT depot in rodents can demonstrate a quick and significant modulation of its thickness in response to application of different physical factors [ 27 ]. Histological pictures of the skin in these mice demonstrated a significant reduction of dWAT thickness with a corresponding thickening of dWAT-free dermis layer. Similarly, UVR 6 weeks, 3 times weekly, minimal erythemal dose of the 8-week-old HR-1 hairless mice with the wavelengths of nm provided significant increase in the thickness and cellularity of dWAT [ 79 ]. Infrared IR radiation with wavelengths up to 1 mm is also able to induce extrinsic skin aging [ 80 , 81 ]. These light waves have much higher penetration depths than UVR and can thus reach the superficial area of sWAT. From this point of view, it would be interesting to compare the modification of dWAT in IR- and UV-irradiated murine skin. In [ 82 ], male Wistar rats were irradiated with IR 1. Skin histology demonstrated abrupt appearance of dermal adipocytes on day 7 after irradiation, with subsequent gradual decrease of their number up to day During the whole observation period, the number of dermal adipocytes was significantly higher in irradiated than in controls. Whereas the action mechanisms of IR and UVR on the skin should to be very different, both types of light seem to have the ability to modify dWAT. Vitamin D can be strongly induced in the skin by UVB radiation [ 83 ]. On the other hand, vitamin D is involved in skin aging, since skin aging demonstrates a U-shaped dependence on vitamin D content [ 84 ]. Even more intriguingly, it was shown that these adipocytes can express the vitamin D receptor and autonomously express 1,dihydroxyvitamin D 3 [ 88 ], suggesting that adipocytes participate in vitamin D production after UVR. The dermal adipose layer in murine skin can be depleted by application of 1,dihydroxyvitamin D 3 in high doses; at the same time, this fat depot significantly expands in the absence of vitamin D [ 89 ]. This effect can be connected with the ability of 1,dihydroxyvitamin D 3 to inhibit the differentiation of murine preadipocytes through suppression of PPARγ [ 90 ]. This reflects the well-known fact that VDR and PPAR signaling pathways are interconnected [ 91 , 92 ]. Contrarily, both hydroxyvitamin D 3 and 1,dihydroxyvitamin D 3 can promote differentiation of human preadipocytes [ 93 ] and mesenchymal cells [ 94 ]. This apparently contradictive influence of vitamin D on the differentiation of murine and human adipocytes still needs to be explained. Whereas it is actually not known whether dermal adipocytes can produce vitamin D, especially after UVR, it is likely that these cells can do so. In this case, it can be supposed that UVB can modulate the dWAT structure also indirectly through induction of vitamin D production in the skin. DWAT can be also modulated indirectly through modification of hyaluronan HA content in the skin. Not only the high-molecular hyaluronan, but also its enzymatic fragments inhibit adipocyte differentiation [ 97 ]. |
| Aging and adipose tissue — Mayo Clinic | u Representative images of immunofluorescence staining of Ki67 in conditioned media treated APC. Blüher M. As obtained from the GO analysis, the differentially expressed genes are included in the mitochondrial-related pathways which particularly aroused our interest, so we next cross-compared these genes with those genes containing thyroid hormone binding site in their open chromatin regions shown in the ATAC-seq. Among the DEGs associated with metabolism-related pathways, we identified seven candidate genes NCF1, NLRP3, DUOX1, IFI30, P2RX1, P2RX6, and PRODH. 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. UVR can significantly modulate the HA content in different compartments of the skin [ 99 ]. |
| Adipose Tissue: Which Role in Aging and Longevity? | Frontiers Research Topic | Correcting pathological Subcutaneous fat and aging deficiencies can also Suvcutaneous in positive metabolic changes. Caloric restriction and aging: controversial issues. Article PubMed CAS Google Scholar Lewoniewska S, Oscilowska I, Forlino A, Palka J. et al. Newcomer ME, Ong DE. |
Subcutaneous fat and aging -
Aging has been shown to be associated with resistance to the anabolic effects of both resistance exercise and meal consumption, as well as resistance to the anticatabolic effects of insulin A substantial portion of the loss of muscle mass and strength with aging is due to reduced physical activity.
Adults who maintain high levels of physical activity into their 60s and above have less body fat and more muscle, are more fit, and are stronger 28 , 70 , That said, even those who maintain such high levels of physical activity suffer declines in fitness and strength over time, indicating a primary aging effect.
Do these primary effects of aging account for the observed insulin resistance with respect to glucose metabolism that has been described in older adults 80? Although insulin resistance with respect to glucose metabolism was once thought to be primarily an effect of aging, it is now known that the greater amounts of body fat 81 and particularly visceral fat 82 are much better predictors of insulin resistance than is age.
In fact, after accounting for body fat and fat distribution, age and fitness do not predict insulin action with respect to glucose metabolism There may also be abnormalities of muscle lipid metabolism associated uniquely with aging, although not as many studies have been done.
In response to leg exercise, leg muscle of older men utilizes more plasma FFA and less intramuscular triglycerides than that of young men The intramyocellular content of ceramides and diacylglycerols, especially of the saturated fatty acid varieties, is greater in older than in younger men Plasma FFA concentrations correlate with intramyocellular lipid content in some thigh muscles; intramyocellular lipid content inversely correlated with measures of strength in young, but not in older, adults In summary, much of the insulin resistance with respect to glucose metabolism that was attributed to aging is, in fact, more strongly related to the tendency for older adults to develop central obesity.
Maintaining a healthy amount of body fat with aging reduces the risk of central obesity—related metabolic disorders, and maintaining high levels of physical activity including resistance exercise can partially offset the progressive loss of muscle mass.
Activation of muscle progenitor cells, or satellite cells, is necessary for muscle regeneration, given that myofibers are terminally differentiated.
Satellite cells exist in a quiescent state between the sarcolemma and basal lamina in muscle. When activated in response to damage or stress, satellite cells proliferate and eventually fuse, forming new myofibers.
A subset of cells reenter the quiescent state, thereby maintaining the progenitor cell pool. In vitro analysis of satellite cells obtained from human muscle indicates that with aging of the individual, satellite cells maintain their capacity to proliferate and differentiate However, immunohistochemical analysis of muscle biopsies indicates that the number of satellite cells per muscle fiber decreases with age Aged human satellite cells also have reduced ability to remain quiescent and exhibit features of cellular senescence including p16 INK4a expression 87 , which may contribute to depletion of the progenitor cell pool over the life span.
In addition to cell-intrinsic factors, age-related changes in the progenitor cell niche, including the extracellular matrix, may also affect the ability to maintain quiescence 88 , 89 Figure 2.
Mitochondrial function, including ATP synthesis and oxidative capacity, decline with aging in skeletal muscle It is not entirely clear whether these changes are related to primary aging or are secondary to decreased physical activity 91 , 92 ; however, recent evidence suggests that both factors contribute 18 , likely to varying degrees between individuals owing to heterogeneity along the life span.
Mitochondrial DNA mtDNA accumulates mutations with aging, and mtDNA copy numbers, which are associated with oxidative capacity, do seem to decrease with aging independent of changes in activity These changes may lead to reduced synthesis of mitochondrial proteins, in turn impacting metabolic capacity.
A number of pathways have been implicated in the muscle atrophy of aging using rodent models. These include activation of activating transcription factor 4 ATF4 , which, through a complex pathway 94 , appears necessary for muscle atrophy to occur with aging mice that lack ATF4 in skeletal muscle fibers maintain muscle strength and mass into old age; ref.
Although how the liver changes with age in humans has not been studied as much as how skeletal muscle and adipose tissue change, the central importance of the liver in metabolic function is such that what is known must be considered.
It has also been reported that older adults are more likely to have increased liver fat and that greater amounts of liver fat are associated with metabolic abnormalities However, the greater amounts of liver fat in older adults may well be explained by their greater tendency to have increased total body and visceral fat.
Most of the differences between younger and older adults with respect to hepatic glucose metabolism can be accounted for by differences in body fat and body fat distribution 82 , although increased hepatic insulin clearance combined with decreased peripheral insulin clearance appears to be linked with aging more than body composition or fitness 82 , Thus, the evidence suggests that the role of the liver in modulating how insulin secretion results in peripheral insulin delivery is directly modulated by aging.
Some of the other factors that may contribute to abnormalities in hepatic metabolism with aging are hormonal changes. In addition to the changes in sex steroids outlined above, aging is associated with delayed and impaired insulin secretion 35 , 98 , greater fasting plasma cholecystokinin CCK and glucagon-like peptide-1 GLP-1 concentrations, and greater CCK and GLP-1 responses to protein ingestion Thus, untangling the roles of hormonal changes that accompany aging from age-specific differences in liver function in humans is not easy.
Caloric restriction CR , the reduction of calorie intake without malnutrition, has been shown to increase life span and improve metabolic health in multiple model systems.
A study of CR in humans the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy [CALERIE] showed weight loss, reduction in total daily energy expenditure, and reduction of the inflammatory markers TNF-α and CRP A follow-up study showed reduction of subcutaneous and visceral abdominal adipose tissue mass as well as less intramyocellular lipid content after calorie restriction Given the beneficial effects of CR, but the considerable effort required to achieve this intervention in the short and especially the long term, much investigation has been conducted into pharmacologic interventions to mimic CR reviewed by Madeo et al.
One of these interventions has been resveratrol. Randomized trials of resveratrol have documented changes in muscle mitochondrial function and adipose gene expression , but no clinically meaningful responses.
As noted above, older adults who exercise regularly have less central body fat, better muscle function, and better insulin sensitivity than sedentary older adults 45 , 66 , 70 , 79 , and exercise training, with or without weight loss, improves muscle mass and function in older adults 26 , Satellite cell content and activation increase in response to exercise — , and data from animal studies are beginning to elucidate the mechanisms by which exercise may improve progenitor cell function Metabolic abnormalities with aging seem to be most readily addressed by aggressive resistance training, which can offset some, but not all, of the anabolic resistance in muscle Thus, of the interventions that have been studied, exercise training appears to have the most wide-ranging benefits when it comes to muscle and adipose tissue health, the latter at least partly through prevention of excess fat gain.
The beneficial effects of resistance exercise on skeletal muscle mass and strength are enhanced by provision of adequate protein intake Increased protein intake is needed for older adults to achieve a response to exercise training similar to that of their younger counterparts, owing to anabolic resistance Leucine supplementation and β-hydroxy-β-methylbutyrate HMB supplementation may be beneficial for increasing muscle mass in older adults with sarcopenia independent of exercise Other nutritional approaches to enhance muscle mass and function with aging include supplementation with omega-3 fatty acids , , although it is unclear through what mechanism this benefit occurs.
Several pharmacologic approaches to improve muscle function with aging have been tried; the outcomes of the resveratrol trials were mentioned above.
Pioglitazone, given in combination with a weight loss program with or without resistance exercise, results in greater loss of visceral fat in older men , and perhaps greater strength gains when combined with resistant training in older women Many preclinical investigations are ongoing to identify mechanisms of age-related muscle atrophy and dysfunction and to test novel therapeutics targeting newly discovered pathways.
For example, therapeutics that target the atrophy mechanisms downstream from ATF4 have included ursolic acid and tomatidine, which promote skeletal muscle hypertrophy 95 and appear to increase mTORC1 activity in skeletal muscle. However, translation to successful clinical applications has so far been limited Senescent cells have emerged as an attractive therapeutic target in the prevention and treatment of age-related and metabolic disease A recent study in humans with diabetic kidney disease demonstrated the ability of senescent cell—targeting, or senolytic, drugs to remove senescent cells from human adipose tissue Further study is needed to determine whether senescence-targeting therapies can improve body composition and metabolic health in aging humans.
Aging is associated with increased adiposity, and the prevalence of obesity is increasing in the older adult population. However, the tendency toward loss of peripheral adipose tissue and the muscle atrophy that accompanies aging cannot be completely prevented.
Adequate dietary protein, perhaps omega-3 fatty acids, and exercise training are the current mainstays of preventing metabolic abnormalities with aging. Correcting pathological hormonal deficiencies can also result in positive metabolic changes.
Therapeutics that mitigate the effects of senescent cell accumulation or target stem cell populations in adipose tissue and atrophy pathways in muscle are on the horizon. These could combine to further improve the metabolic health of older adults.
This work was supported by NIH grants, DK and DK The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Conflict of interest: AKP is a listed inventor on patents on senolytic drugs held by Mayo Clinic, USA1 and USA1. Copyright: © , Palmer et al. This is an open access article published under the terms of the Creative Commons Attribution 4. Reference information: J Clin Invest. Go to JCI Insight.
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Single-cell sequencing of human white adipose tissue identifies new cell states in health and obesity. Spallanzani, R. Distinct immunocyte-promoting and adipocyte-generating stromal components coordinate adipose tissue immune and metabolic tenors.
Download references. This work was supported by the National Natural Sciences Foundation of China T, We would like to thank The Core Facilities of Zhejiang University-University of Edinburgh Institute for technical assistance. Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, , China.
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Wenyan Zhou, Junxin Lin, Yuemin Ou, Hongwei Wu, Yiyang Yan, Aaron Trent Irving, James Q. Department of Plastic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, , China. The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, , China.
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Conceptualization by H. Lou; Methodology by W. Lin, and H. and J. Lin; Review and Editing, Y. Correspondence to Hongwei Ouyang.
Human adipose tissues were obtained from patients undergoing specific surgical procedure with the approval of the ethics committee of Second Affiliated Hospital, Zhejiang University Approval number: and General Hospital of Ningxia Medical University Approval number: KYLL Open Access This article is licensed under a Creative Commons Attribution 4.
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We also found Pu. We identify an ARC population and its capacity to inhibit differentiation of neighboring adipose precursors, correlating with aging-associated loss of SAT. Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies.
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Download PDF Main PDF. Email Facebook. Aging-dependent regulatory cells emerge in subcutaneous fat to inhibit adipogenesis.
Abstract Adipose tissue mass and adiposity change throughout the lifespan. Download PDF to View View Larger. For improved accessibility of PDF content, download the file to your device. Thumbnails Document Outline Attachments.
Adipose Subcutaneous fat and aging aginy and adiposity change throughout the lifespan. During Subvutaneous, while visceral Subcutaneojs tissue Subcutaneous fat and aging tends to increase, peripheral subcutaneous adipose tissue SAT decreases significantly. Unlike VAT, which is linked to metabolic diseases, including type 2 diabetes, SAT has beneficial effects. However, the molecular details behind the aging-associated loss of SAT remain unclear. Here, by comparing scRNA-seq of total stromal vascular cells of SAT from young and aging mice, we identify an aging-dependent regulatory cell ARC population that emerges only in SAT of aged mice and humans.
Thank ahing for visiting nature. You Peppermint tea recipe using a browser version with limited support for CSS. To Subcutaneous fat and aging Sjbcutaneous best experience, we recommend you use a more Subcutnaeous to date Organic mineral supplements or turn off Subcutandous mode in Subcutaneous fat and aging Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Age-dependent adipose tissue malfunction raises the risk of diseases like diabetes, cardiovascular disease, and even cancer by contributing to metabolic decline, heterotopic fat storage, and chronic systemic inflammation. Although the heterogeneity of the cell population during mouse aging has been studied, 2 little is known about the cellular and molecular basis of human adipose tissues aging. Subcutaneous fat and aging -
The SAT was collected from the navel side of the midabdomen, immediately placed into liquid nitrogen, and transferred to °C for storage.
The characteristics of the study group are shown in Supplemental Tables 1, and whole genome analysis was performed on all samples. Tissue weigh approximately 60 mg in liquid nitrogen was pestled into powder in a 2 mL tube, then homogenized for 2 min, followed by 5 min rested horizontally.
The mixture was centrifuged at 12,×g at 4 °C for 5 min, and the supernatant was then transferred into another EP tube containing 0. The mixture was shaken vigorously for 15 s and centrifuged for 10 min at 12,×g at 4 °C. After centrifugation, the upper aqueous phase containing the RNA was transferred into another tube with an equal volume of supernatant of isopropyl alcohol, after which, the mixture was put under centrifugation at 13, rpm for 20 min at 4 °C.
The pellet was air dried in the biosafety cabinet for 5—10 min. Subsequently, the RNA pellet was dissolved by 25— µL of DEPC-treated water. Eventually, total RNA was quantified and qualified using a NanoDrop and Agilent bioanalyzer Thermo Fisher Scientific, MA, USA.
RNase H was used to remove rRNA, and DNase I was used to digest double-stranded and single-stranded DNA in total RNA. Purified RNA from previous steps was fragmented into small pieces with fragment buffer at an appropriate temperature. First-strand cDNA was generated using First Strand Master Mix by PCR, and second-strand cDNA was also generated.
The reaction product was purified by magnetic beads. A-Tailing Mix and RNA Index Adapters were then added for end repair. The cDNA fragments were amplified with adapters by PCR, and the products were purified by Ampure XP Beads.
The library was validated on an Agilent Technologies bioanalyzer for quality control. The double-stranded PCR product from the previous step was heat denatured and circularized by the splint oligo sequence. The single strand circle DNA was formatted as the final library. The final library was amplified with phi29 Thermo Fisher Scientific, MA, USA to generate DNA nanoballs DNBs , which had more than copies of one molecule.
DNBs were loaded into the patterned nanoarray, and single-end base reads were generated on the BGISEQ platform BGI-Shenzhen, China. The data of sequencing were screened with SOAPnuke v1. Then, we obtained and saved the clean reads in FASTQ format. HISAT2 v2. The clean reads were aligned to the reference coding gene set using Bowtie2 v2.
According to the gene expression of different samples, the heatmap was generated by pheatmap v1. By using DESeq2 v1. Fresh tissue sample is flash frozen by liquid nitrogen and then ground completely.
The transposition reactions are initiated by adding transposase. The PCR reaction system is configured to initiate PCR amplification of the transposition products. The corresponding library quality control protocol will be selected depending upon product requirements.
Single-stranded PCR products are produced via denaturation. The reaction system and program for circularization are subsequently configured and set up. Single-stranded cyclized products are produced, while uncyclized linear DNA molecules are digested.
Single-stranded circle DNA molecules are replicated via rolling cycle amplification, and a DNA nanoball which contain multiple copies of DNA is generated. Sufficient quality DNA nanoballs are then loaded into patterned nanoarrays using high-intensity DNA nanochip technique and sequenced through combinatorial Probe-Anchor Synthesis.
Cells reached complete differentiation after a total of 6 days. The entire cycle lasted for 10 days. The methods were performed in accordance with the approved guidelines of the Animal Care and Use Committee of Nanjing Medical University.
The experimental protocols were approved by the Animal Care and Use Committee of Nanjing Medical University. Total RNA from the fully differentiated adipocytes was extracted using the lipid RNeasy kit and the RNeasy mini kit Qiagen. The sequences of the primers are shown in Supplemental Table 2.
The ratio of the target gene to the copy number of the internal reference in each sample was used to represent the relative expression level of the target gene. Fresh adipose tissue was retrieved from another group of patients, the same as the sample used in the validation experiment, and was cultured in well plates and differentiated as indicated Seahorse Bioscience, North Billerica, MA.
The medium was replaced with prewarmed unbuffered DMEM DMEM basal medium supplemented with 25 mM glucose, PH7. The residual OCR was considered nonmitochondrial respiration. Cells were visualized and imaged under 20× magnification by fluorescence microscopy Olympus, Tokyo, Japan.
Q-value was applied in the screen of significantly enriched pathways, the Q-value is an adjusted p-value, taking in to account the false discovery rate FDR , an FDR-adjusted p-value aka a q-value of 0.
by p-value will be false positives. To explore the specific mechanism of how SAT affects aging, we analyzed the differential expression of RNA sequences in the SAT of 3 young men and 3 old men.
A volcano plot of the expressed genes was generated Fig. There were 17, genes in both young and old SAT, among them, genes showed significantly higher expression in the SAT of elderly individuals, and genes showed lower expression in the SAT of the elderly Fig.
To further understand the possible functional implications of these gene expression characteristics, KEGG and GO analyses of these differentially expressed genes were performed.
The upregulated differentially expressed genes of aged subcutaneous fat were enriched in the MAPK signaling pathway, lipid metabolism, and fatty acid metabolism Fig. The downregulated differentially expressed genes were included in the fatty acid degradation and oxidative thermogenesis pathway Fig.
In addition, GO analysis showed that the upregulated genes were enriched in the processes of lipid synthesis and storage, oxygen transport, ATP generation, ROS production, and oxidative stress Fig. Thus, these findings indicated that several functional pathways are involved in the development of aging.
Genome characterization. A Volcano plot of differentially expressed genes. Upregulated genes are shown by red dots, and downregulated genes are shown by green dots.
B Venn diagram showing 17, genes expressed both in the elderly and young SAT, with genes upregulated and genes down regulated in the common zone. KEGG pathway enrichment analysis A Upregulated gene enrichment in signaling pathways.
B Downregulated gene enrichment in signaling pathways. The enrichment factor was defined as the ratio of the number of differential genes enriched in the pathway to the number of annotated genes.
GO-P enrichment analysis A Upregulated gene enrichment in biological processes. B Downregulated gene enrichment in biological processes. TO further understand the functional associated changes in SAT, considering the GO analysis results, we selected the aimed at the pathways linked with mitochondrial damage, mitochondrial dysfunction, and ROS accumulation.
We first conducted an oxygen consumption experiment on SAT at different ages. Consistent with the inhibition of mitochondrial functional gene expression in aging subcutaneous adipose cells, the oxygen consumption rate OCR of old subcutaneous adipose cells was lower than that of young subcutaneous adipose cells under basal conditions.
However, there were no significant differences in nonmitochondrial respiration [rotenone] Fig. Immunofluorescence staining on frozen SAT sections demonstrated that old SAT contained more ROS and less mitochondria than young SAT Fig. Thus, these findings indicated that ROS accumulation may be related to impaired mitochondrial function in the SAT of elderly individuals.
Measurement of O2 consumption and immunofluorescence staining. A OCRs were quantified in adipose tissue under basal conditions Basal or with rotenone Rot disrupting the respiratory chain.
B ROS in frozen sections of human subcutaneous fat were stained by immunofluorescence. Nuclei were counterstained with DAPI.
Fluorescence intensity was quantified using densitometric image analysis software with cell quantity adjustment. C Mitochondria in frozen sections of human subcutaneous fat were stained by immunofluorescence. To understand the specific mechanisms by which differentially expressed genes regulate adipose tissue, we also investigated open chromatin mass spectrometry of human SAT.
To gain a genome-wide view of accessible chromatin regions from the isolated adipocytes, we utilized an assay for Transposase-Accessible Chromatin followed by sequencing ATAC-seq. The chromatin was fragmented by Tn5 transposase into nucleosome-free, mono-nucleosome, and di-nucleosome patterns, and the similar distribution of fragment sizes suggested that chromatin was accessible to Tn5 transposase to the same degree in all samples independently among different groups Fig.
In addition, we found that the ATAC-seq signal was mainly concentrated in the intergene region Fig. 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.
The results showed that the proportion of the promoter region UP2K in the regions accessible to chromatin was altered at different ages Fig. ATAC-seq chromatin accessibility analysis in young and old SAT. A Distribution of ATAC-seq fragment size in SAT.
B Chromatin accessibility around the TSS in SAT. C Relative proportions of gene coding regions, intergenic regions, introns, exons, upstream regions, and downstream regions.
To examine the correlation between depot-specific open chromatin regions from the ATAC-seq analysis with depot-specific gene expression signatures, we integrated the ATAC-seq with RNA-seq datasets. Nowadays, more and more researches point out that the aging-related diseases are linked with impaired cell metabolism and mitochondrial dysfunction.
As obtained from the GO analysis, the differentially expressed genes are included in the mitochondrial-related pathways which particularly aroused our interest, so we next cross-compared these genes with those genes containing thyroid hormone binding site in their open chromatin regions shown in the ATAC-seq.
Eventually we concluded 7 differentially expressed genes associated with mitochondrial function, and with thyroid hormone receptors and their co-transcription factor-binding sites located in their open regions.
A previous study has reported that the RARa retinoic acid receptors RARs , a distinct class of nuclear receptors, are also efficient heterodimer partners for thyroid hormone receptors THRs and that RARs also serve as robust heterodimer partners and combinatorial regulators of T3-modulated gene expression [ 20 ].
In the present study, THRb and RARa accounted for a relatively high proportion in young SAT samples with approximately At the same time, the THRb and THRa thyroid hormone receptors accounted for a relatively low proportion in old SAT samples with approximately We also performed de novo motif analysis of specific open chromatin regions in these samples and confirmed the expression of thyroid hormone-related receptors binding sites Fig.
Cross-comparing the RNA-seq and ATAC-seq, we identified seven significant target genes as follows: the expression of Neutrophil cytosolic factor-1 NCF1 , a crucial component of nicotinamide adenine dinucleotide phosphate NADPH oxidase, and NOD-like receptor thermal protein domain associated protein 3 NLRP3 which is involved in the production of ROS related inflammation, and Dual oxidase 1 DUOX1 ,a member of the protein family of nicotinamide adenine dinucleotide phosphate NADPH oxidase, increased with age in SAT; and the expression of Interferon Gamma Inducible Protein 30 IFI30 ,a gene plays an important role in recycling GSH in order to neutralize ROS, and purinergic receptor P2X, ligand-gated ion channel 1 and 6 P2RX1 and P2RX6 , critical for autophagy, and Proline Dehydrogenase PRODH , a mitochondrial flavin enzyme, decreased with age in SAT.
Furthermore, the regions around these target genes gained open chromatin architecture in both young and old SAT, all of which had altered accessibility to the thyroid hormone-related receptors in their chromatin open region of different age Fig. Association between the specific chromatin-accessible regions and gene expression in SAT.
A Proportion of thyroid hormone receptors THRb and their co-transcription factor-binding sites RARa in the open chromatin region of related genes in the young SAT. B Proportion of thyroid hormone receptors THRa,THRb in the open chromatin region of related genes in the old SAT.
C Enriched motif matrices are presented along with the p values. D Gene-specific open chromatin regions in SAT at different ages. The characteristics of the study group are shown in Supplemental Table 3.
The expression levels of NCF1, NLRP3, and DUOX1 were increased in old subcutaneous adipocytes compared to young samples, whereas IFI30, P2RX1, P2RX6, and PRODH were highly expressed in young subcutaneous adipocytes. The results were in accordance with the RNA-seq dataset Fig.
Validation of specific gene expression and its correlation with thyroid hormone regulation. A Young, subcutaneous adipose tissue of young individuals; old, subcutaneous adipose tissue of old individuals.
Compared to the SVF cells of SAT without T3 stimulation, the gene expression in the primary cells stimulated by the physiological dose and supraphysiological dose of T3 significantly and gradually increased Fig. Therefore, we hypothesized that adipose tissue-specific thyroid hormone signaling regulates genes involved in subcutaneous adipocyte senescence.
Aging is the single greatest cause of disease and death worldwide, and understanding the associated processes may vastly improve quality of life [ 9 ].
The distribution of adipose tissue significantly changes with age, and this type of adipose tissue redistribution in elderly individuals is associated with an increased risk of metabolic syndrome diabetes, hypertension, dyslipidemia, atherosclerosis, and increased intra-abdominal fat [ 4 ].
Using an in vivo fat transplantation strategy, some researchers have demonstrated that SAT adipose tissue has direct and beneficial effects on the control of body weight and metabolism [ 7 ].
To explore the changes that occur in SAT with age, we conducted RNA-seq on SAT at different ages. In the present study, we found that the SAT function of elderly individuals was damaged, and the pathways enriched in the GO-analysis are mainly associated with DNA damage, inflammation, fibrosis, mitochondrial damage, mitochondrial dysfunction, and ROS accumulation.
Immunofluorescence staining demonstrated that mitochondria in the SAT of elderly individuals decreased and ROS accumulated. Measurement of the oxygen consumption rate OCR further confirmed that SAT respiration in elderly individuals was reduced.
Therefore, these findings indicated that SAT undergoes mitochondrial metabolism changes during aging. RNA-seq screened differentially expressed genes DEGs at the mRNA level, and these gene functions were related to mitochondrial metabolism.
Although we demonstrated that the mitochondrial function of SAT changes during aging, the mechanism of aging-related changes in SAT remained unclear.
To express genes, chromatin must be in an open conformation. Open chromatin allows regulatory proteins to bind to DNA and regulate DNA function. h UMAP visualization of all APC subpopulations.
RNA-velocity analysis with velocity field projected onto the UMAP plot of APC subpopulations, arrows show the local average velocity evaluated on a regular grid and indicate the extrapolated future states of cells top. Cells were annotated by monocle pseudotemporal dynamics purple to yellow, below.
i , j APC populations of the second cohort. i Scatter plot shows the changes in the proportion of 6 APC subpopulations during SAT aging process. of 4 young and 4 old individuals from the second cohort.
j Dot plot shows the expression levels of chemokine activity-related genes and adipogenic-related gene across 6 APC subpopulations of 4 young and 4 old individuals from the second cohort. k qRT-PCR for PLAU expression level of human APC after PLAU knockdown.
of three biological repetitions. l Representative images of SA-β-gal staining of human APC upon shRNA-mediated knockdown of PLAU. Positive signals were quantized by average optical density AOD. of 3 fields of each group. m Representative images of Oil Red staining shows the adipogenic differentiation capacity of human APC upon shRNA-mediated knockdown of PLAU.
of 3 cell wells of each group. n Representative images of immunofluorescence staining of Ki67 in human APC upon shRNA-mediated knockdown of PLAU. of 4 fields of each group. o Re-clustering of IC1-IC3 in a , b identified 8 specific immune cell subpopulations, samples from 3 young individuals and 3 old individuals.
p Dot plot shows the expression levels of representative cell-type-specific marker genes across all these 8 immune cell subpopulations. q Interaction heatmap plots the total number of cell receptor y axis and ligand x axis interactions in 3 young donors left and 3 old donors right derived SAT.
The color key from blue to red indicates low to high number of interactions. s — u Primary human APC treated with conditioned media from DOX-induced senescent macrophages.
s Representative images of SA-β-gal staining of conditioned media treated APC. of 3 fields. t Representative images of Oil Red staining show the adipocyte differentiation of conditioned media treated APC. of 3 biological replications. u Representative images of immunofluorescence staining of Ki67 in conditioned media treated APC.
In dot plot d , j , p , the size of the dot corresponds to the percentage of cells expressing the specific gene in each cluster, and the color encodes the scaled average expression level of feature genes across all cells within a subpopulation.
Interestingly, it was noted that the cell number of inflammatory APC5 increased significantly with aging Fig. Analysis of aging-dependent differentially expressed genes showed that the expression level of cell surface markers PLAU and THBD were significantly increased in aged APC5 Fig.
Immunofluorescence staining and flow cytometry of human adipose tissues based on PLAU and THBD verified the accumulation of APC5 in old individuals Fig. These findings indicated that human SAT contain a subset of defective inflammatory APC population that accumulates with aging.
In scRNA-seq analysis on SAT from another independent cohort of young and aged donors, we also identified inflammatory APC populations APC3 and APC4 that accumulate with age and exhibit higher levels of PLAU and THBD expression, further supporting the notion.
supplementary Fig. S3 , Fig. As one of the biomarkers of APC5, PLAU was also predicted as a frailty marker in previous study. Thus, we speculated that PLAU might be involved in the progression of APC aging. To test this hypothesis, we firstly measured the expression level of PLAU in human primary APC derived from young year-old and old year-old individuals.
The qRT-PCR results showed that PLAU expression level was positively correlated with donor age supplementary Fig. Additionally, the adipogenic differentiation capacity of APC from elderly individuals was significantly lower than that of young individuals supplementary Fig.
Senescence-associated β-galactosidase SA-β-gal staining showed that overexpression of PLAU overexpressing efficiency, S5c, d. Next, we investigated whether down-regulation of PLAU could rescue APC aging.
Knockdown of PLAU silencing efficiency, Collectively, these results suggested that aberrant expression of PLAU promotes APC aging, and may represent a promising therapeutic target for aging related diseases of human adipose tissues.
Previous studies showed that adipose tissue functions are tightly regulated by the crosstalk between APC and immune cells.
Re-clustering of IC1-IC3 cells identified 8 specific immune cell subpopulations ICS ICS1, ICS3, ICS6 showed gene expression signatures of distinct T cell subpopulations Fig. While ICS6 expressed higher levels of the early T cell activation markers CD69 and CXCR4 , ICS1 was distinguished from ICS6 by high expression levels of ribosomal protein-related genes, representing a proliferating cell population supplementary Table S5.
ICS5 was identified as M2-like macrophage by the expression of CD , and ICS7 was recognized as M1-like macrophage for high expression level of FCGR3A Fig. After cell type annotation, we utilized CellPhoneDB and iTALK to perform unbiased ligand-receptor interaction analysis between the ICS and APC.
Both algorithms demonstrated that M1-like macrophage ICS7 maintained a relatively strong interaction with other cell subpopulations Fig. Particularly, iTALK analysis showed that aging shifts the intercellular chemokine crosstalk from an APC-dominating pattern to an M1-like macrophage-dominating pattern Fig.
To study whether the macrophage-dominating interaction pattern contributes to APC dysfunction, we cultured human primary APC derived from young individuals with conditioned medium of Doxorubicin DOX -induced senescent M1 macrophages supplementary Fig.
S6a, b. Two years of DHEA replacement in older males and females with low serum DHEA concentrations had no effect on systemic FFA metabolism Thus, the majority of the changes in adipose tissue lipolysis with aging appear to be more related to the greater central adiposity that is seen in older adults, rather than hormonal changes.
The other aspect of adipose tissue function that can relate to metabolic abnormalities with aging is the ability of adipose tissue to store fatty acids. First, changes in regional storage can potentially contribute to changes in body fat distribution.
Second, reduced efficiency of fat storage results in greater postprandial chylomicronemia that can shunt dietary fatty acids into lean tissues, where they compete with glucose as a metabolic fuel. Meal fat storage in adipose tissue is less in older adults than in the young 24 , whereas meal fat oxidation, which occurs in lean tissues, is greater in older adults Different adipose depots have different abilities to store fatty acids 41 , 42 , and there are sex-specific patterns of fatty acid storage 20 , Typically, there is a preferential storage of meal fat in upper body compared with lower body adipose tissue in young, healthy men and women Additional evidence for the effects of sex steroids on adipose tissue function comes from the finding that postmenopausal women have greater fatty acid storage in total and lower body subcutaneous adipose tissue than age-matched premenopausal women This effect appears to be related to greater increases in abdominal adipose tissue lipoprotein lipase activity in response to meals 44 and greater abdominal adipose tissue activity of one of the key enzymes in triglyceride synthesis, diacylglycerol acyltransferase Interestingly, in this study the greater adipose meal fat storage in postmenopausal females was accompanied by lesser postprandial fat oxidation than in premenopausal females In men, testosterone deficiency results in greater storage of meal fat and endogenous fatty acids in lower body subcutaneous fat, which is associated with increased regional adipose tissue acyl-CoA synthetase activity Thus, changes in the tendency of older adults to store dietary fat are both region- and sex-specific.
Uncoupling the effects of aging, hormonal changes, and body fat gain on these functions is not easy, and only with the more severe peripheral lipoatrophy of aging is there perhaps a clearer case to be made for aging per se.
Several approaches have been used to understand the cellular nature of these changes. For example, there is some evidence that reduced physical activity contributes to adipose tissue dysfunction in older adults; physical activity training reduced some indices of adipose tissue inflammation in older women However, the extent to which adipose tissue inflammation in humans contributes to adipose tissue dysfunction with regard to one of its main roles — lipolysis — has recently been questioned Other approaches include the study of isolated adipocytes collected from older adults.
For example, reduced ex vivo lipolysis has been found when adipocytes from older adults are studied 27 , 29 , although Nicklas et al.
did not observe that differences in ex vivo lipolysis measures were reflected in changes in plasma FFA concentrations It may be that the greater body fat content and, perhaps, in vivo adipose insulin resistance 46 explain the apparent disconnect between in vivo and ex vivo studies; studies of adipocytes collected from older adults may not reflect whole-body physiology.
Another helpful technique to study adipose function with aging is the study of adipose stem cells. Adipose progenitors isolated from older adults exhibit diminished proliferative and migratory capacity, reduced ability to incorporate lipids, increased oxidative stress, and features of cellular senescence 25 , 47 — 50 Figure 2.
Cellular senescence and progenitor cell function may directly diminish the ability of subcutaneous adipose tissue to store lipids in aging 51 , Comparisons of subcutaneous versus visceral adipose progenitors have been done in model organisms; however, more research is needed to determine whether differences between depots in humans can explain the redistribution of adipose tissue in human aging.
Cellular changes in adipose and skeletal muscle with aging. Immune cell infiltration increases with age, and accumulation of aging-dependent regulatory cells is seen. In skeletal muscle, mitochondrial function is decreased with aging, satellite cells lose ability to maintain quiescence, and myocytes undergo atrophy.
Recently, a novel subpopulation of cells named aging-dependent regulatory cells ARCs was identified through single-cell RNA-Seq analysis of subcutaneous adipose tissue ARCs are proinflammatory and inhibit differentiation and proliferation of neighboring progenitor cells, but are distinct from senescent cells in that they can proliferate.
Interestingly, these cells were found only in subcutaneous, and not in visceral, adipose tissue in mice. It is not yet known whether they exist in visceral adipose tissue in humans.
Nguyen et al. Adipose tissue is composed of not only adipocytes and adipocyte progenitor cells, but a complex milieu of immune cells including but not limited to NK cells, T cells, eosinophils, and macrophages.
Proinflammatory immune cells accumulate in adipose tissue with aging and have been linked to development of systemic chronic low-grade inflammation. There are limited data in humans regarding the effects of aging on adipose immune cell composition and function.
Eosinophil abundance in human adipose tissue appears to have a negative correlation with age, and studies in mice indicate that eosinophils may play a role in mitigating age-related adipose tissue inflammation Adipose tissue macrophage abundance correlates with adiposity as well as adipocyte size and therefore may be expected to increase with aging.
However, many studies describing this association were conducted in the context of obesity, and therefore the impact of aging alone is unknown 55 , Adipose tissue plays a major role in endocrine signaling via secretion of adipokines.
One such adipokine, adiponectin, which is associated with lower risk of metabolic syndrome in older adults 57 , 58 , is increased in centenarians and their children compared with non-centenarians Data from animal models suggest that maintenance of adiponectin levels promotes metabolic health and prolongs life span However, some studies in humans have shown a relationship between higher adiponectin levels and sarcopenia, frailty, and even mortality 61 — There is some speculation that higher levels of adiponectin may be secondary to compensatory mechanisms in response to inflammation and oxidative stress, or may be related to adiponectin resistance, but further study is needed to clarify these points.
Skeletal muscle is an important tissue for glucose and fatty acid metabolism, as well as a major site of body protein. This difference is even more evident when imaging techniques such as CT or MRI are used. Cross-sectional comparisons between young and older study participants suggest that by age 60 humans will lose approximately 0.
Thus, muscle loss includes both locomotive and postural muscles. Together with loss of muscle mass, there is often an increase in intramuscular adipose tissue 68 — so-called marbling. This is to be distinguished from intramyocellular lipids, which have also been reported to be increased with aging 10 , 70 , Intramuscular adipose tissue is a marker of, but unlikely to be a major cause of, muscle dysfunction.
This is because intramuscular adipocytes, when present, are adjacent to blood vessels outside the perimysium; that is, there are no adipocytes inside muscle fascicles Because there is no portal system in skeletal muscle, intramuscular adipocytes are unable to provide fatty acids or lipokines to myocytes directly.
The lesser amount of skeletal muscle in older adults is accompanied by reduced muscle function. There are progressive declines in peak VO 2 ref.
The loss of strength 2. An autopsy study indicated that muscle atrophy begins around 25 years of age and thereafter accelerates owing to a loss of fibers more than to a reduction in fiber size 76 , although others have suggested that reduced fiber size is a more important determinant of muscle atrophy The loss of muscle has implications for both mobility and metabolic regulation muscle is the primary site of insulin-mediated glucose storage and oxidation , making the physiological explanation for age-related muscle loss an important area of study.
Muscle proteins are constantly turning over; older, damaged proteins are replaced by newly synthesized proteins. Normally, muscle protein synthesis anabolism is stimulated by meal consumption and resistance exercise The amino acids, especially leucine, provided by meal consumption are thought to be the main drivers of this anabolic response.
The combination of resistance exercise and meal protein consumption is synergistic with respect to muscle protein synthesis Insulin acts to restrain muscle protein breakdown, even in the fasting state Aging has been shown to be associated with resistance to the anabolic effects of both resistance exercise and meal consumption, as well as resistance to the anticatabolic effects of insulin A substantial portion of the loss of muscle mass and strength with aging is due to reduced physical activity.
Adults who maintain high levels of physical activity into their 60s and above have less body fat and more muscle, are more fit, and are stronger 28 , 70 , That said, even those who maintain such high levels of physical activity suffer declines in fitness and strength over time, indicating a primary aging effect.
Do these primary effects of aging account for the observed insulin resistance with respect to glucose metabolism that has been described in older adults 80? Although insulin resistance with respect to glucose metabolism was once thought to be primarily an effect of aging, it is now known that the greater amounts of body fat 81 and particularly visceral fat 82 are much better predictors of insulin resistance than is age.
In fact, after accounting for body fat and fat distribution, age and fitness do not predict insulin action with respect to glucose metabolism There may also be abnormalities of muscle lipid metabolism associated uniquely with aging, although not as many studies have been done.
In response to leg exercise, leg muscle of older men utilizes more plasma FFA and less intramuscular triglycerides than that of young men
Kruglikov ILScherer PE. Skin Suubcutaneous are adipocytes the next Subcutaneous fat and aging. Aging Subcutanous NY. Copyright: © Kruglikov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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