Does Obesity Literally Accelerate Aging?
It is well known that carrying excess visceral fat tissue increases risk of age-related disease, shortens life expectancy, and raises lifetime medical expenditure. The more fat tissue, the worse the outcome, but even being modestly overweight rather than obese still produces a negative impact on long term health. This is the story told in a great many epidemiological studies with large patient populations. Does this mean that obesity accelerates aging, however? It might be surprising to find out that this isn't a question that has an easy or a straightforward answer.
In order to talk about whether aging is accelerated, one has to have a strong understanding of what causes aging. If we can list specific causative mechanisms of aging, and then measure their state, then we might be able to say whether or not aging is accelerated or slowed by a given circumstance. In the SENS view of aging, the root cause is accumulation of cell and tissue damage that arises as a side-effect of the normal operation of cellular metabolism. Things like the presence of lingering senescent cells or cross-links in the extracellular matrix. We can make the argument that a lifestyle choice that increases the pace at which senescent cells emerge in tissues is in fact an acceleration of aging. We can similarly argue that environmental circumstances such as smoking or chemotherapy that do the same have some component of accelerated aging in the harm that they cause.
Excess visceral fat tissue does in fact add to the presence of senescent cells. It also causes chronic inflammation via several other mechanisms, distinct from that of the inflammatory signaling produced by senescent cells. The chronic inflammation of aging is a downstream consequence of causes of aging, but it is a prominent feature of aging and causes further issues in and of itself, speeding up the progression of all of the common age-related conditions. Could upregulating inflammation directly, without going via one of the underlying causes of aging, be called an acceleration of aging? Perhaps not. Perhaps it should just be called harm and damage, and fall into the same category as breaking a bone and the long-term consequences that result from that sort of injury. So we might say that fat tissue accelerates aging in some senses, but in others it is not an acceleration of aging, just a harm.
This may be a matter of semantics and definitional games. The lesson at the end of the day is to avoid putting on excess weight, as even therapies targeting the causes of aging cannot prevent all of the long-term damage that being overweight will generate. Different perspectives are always interesting, however. Today's open access paper, noted below, looks at the question of whether or not obesity accelerates aging through the filter of the Hallmarks of Aging, a more recent catalog of potential causes and mechanisms of aging that overlaps to some degree with the causes of aging listed in the SENS proposals, but has significant differences. Some of the Hallmarks are clearly downstream consequences or markers of the progression of aging from the SENS perspective, for example.
Obesity May Accelerate the Aging Process
It has been suggested that obesity not only increases the onset of metabolic imbalances, but also decreases life span and impacts cellular processes in a manner similar to aging. A defining characteristic of aging is the gradual loss of physiological integrity, which results in increased vulnerability to disease and death. This loss of physiological integrity underlies multiple pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative disease. Recently, nine hallmarks which define the aging process have been described. We will briefly discuss each of the hallmarks of aging and the potential interactions between each hallmark and obesity.
Based on the evidence, two distinct hypotheses can be proposed. One is that the cellular responses provoked by an excess of nutrients cause obesity, and that obesity is responsible for accelerating the pace of aging. Supporting this hypothesis are the observations that knocking out the fat-specific insulin receptor, to produce extremely lean mice, and removal of visceral fat in rats increased life span; additionally, calorie restriction on lean strains of rats, had only a minor effects on lifespan. The alternative possibility is that the cellular responses provoked by an excess of nutrients are responsible for increasing the pace of aging. This common soil shared by both aging and obesity has been named "adipaging", and there is some evidence of commonalities: hyperglycaemia, for example, induces senescence and the SASP in endothelial cells and macrophages while glucose reduction prevents replicative senescence in human mesenchymal stem cells.
Telomere Attribution
Obesity causes oxidative stress and inflammation, which may increase the rate of telomere shortening. Although the association is weak or moderate, results show a trend toward a negative association between obesity, in particular central obesity, and telomere length. Human studies indicate that telomere shortening is directly correlated to adiposity, and telomere length is inversely associated with BMI. However, this association is not linear across the age and it is stronger in younger compared to older individuals. We feel that although the results cumulatively show a tendency toward an inverse correlation between obesity and telomere length; it is more prudent to conclude that the available studies are heterogeneous and show a weak statistical significance.
Epigenetic Alteration
Several studies demonstrated that obesity is associated with extensive changes in gene expression in multiple tissues and that increased BMI is associated with an altered methylation of specific genes. For instance, it was shown that obesity is associated with methylation changes in blood leukocyte DNA that could lead to immune dysfunction. Investigation of the association between BMI and epigenetic age in blood cells demonstrated that BMI is positively associated with epigenetic aging in middle-aged individuals. The impact of obesity on epigenetic aging is also described: obesity accelerates epigenetic changes associated with aging in the human liver resulting in an apparent age acceleration of 2.7 years for a 10-point increase in BMI, supporting the idea that obesity may accelerate the aging process.
Mitochondrial Dysfunction
Obesity has also been associated with mitochondrial dysfunction. Calorie restriction, conversely, which increases longevity, maintains mitochondrial function. Several studies showed that obesity induces a reduction in mitochondrial biogenesis and a decreased mitochondrial oxidative capacity in adipocytes of both rodents and humans. In obese individuals, reduced mitochondrial biogenesis is associated with metabolic alterations, low-grade inflammation, and insulin resistance. Several lines of evidence suggest that obesity induces a shift toward a fission process linked to mitochondrial dysfunction in liver and skeletal muscle. In skeletal muscle of obese mice, an increased mitochondrial fission was observed and the activity of protein involved in mitochondrial dynamic was altered. Aging and obesity appear superimposable in their impact on mitochondria and it is reasonable to hypothesize that they could exert additive effects.
Cellular Senescence
It has been demonstrated that SA β-gal+ cells are more abundant in pre-adipocyte and endothelial cells isolated from obese compared to lean rats and human, moreover there is a positive correlation between BMI and adipose tissue SA β-gal activity and p53. There is an accumulation of senescent T cells and an increased number of macrophages in the inflammatory foci of the visceral adipose tissue of obese mice, and obese mice accumulate senescent glial cells in the brain. There appears to be a strong relationship between obesity and senescence. Obesity may promote the aging process by inducing senescence. Conversely, senescence and the resulting pro-inflammatory secretory phenotype could contribute to the morbidity associated with obesity and plays a role in the development of insulin resistance and diabetes. There is a vast literature in support of this view.
Deregulated Nutrient Sensing
In biogerontology, the IIS and mTOR pathway are considered "accelerators" of the aging process. There is accumulating literature suggesting that in obesity, these pathways are over-activated. In contrast, there is also accumulating literature showing that pro longevity pathways, such as the AMPK and sirtuins pathways are dampened by obesity. In conclusion, there is solid evidence that obesity deregulates cellular mechanisms related to nutrient sensing.
Altered Intercellular Communication
It is accepted that aging impacts the organism at the cellular level, but also decreases the capacity of cells of an organism to interact. During aging, there is a decreased communication at the neuronal, neuroendocrine, and endocrine levels. Two of the most compelling examples of impaired communication are inflammaging and immunosenescence. The inflammaging phenotype results in elevated cytokines. These cytokines can accelerate and propagate the aging process. The literature persuasively suggests that the accumulation of pro-inflammatory cells, in the adipose tissue of obese patients, through cytokines and extracellular vesicles, accelerates the rate of aging both in the adipose tissue itself and the entire organism.
Genomic Instability
The impact of obesity on genomic instability has been analyzed. Results from animal studies and studies in humans, monitoring DNA damage in lymphocytes and sperm, were analyzed. However, heterogeneity in the study design, methodology, and confounding factors, preclude the conclusion that an association exists between obesity and DNA damage. Nevertheless, the causal relation between excess of body weight and genomic instability is supported by mechanistic studies. Oxidative damage seems as the one mechanism regarded as the most relevant.
Loss Of Proteostasis
With age, the ability of many cells and organs to preserve proteostasis under resting and stressful conditions is gradually compromised. Key pathways affected by the aging process alter components of the proteostasis machinery, e.g., by inducing reduction of chaperones or proteasomal degradation. Obesity can induce prolonged or chronic unfolded protein response possibly mediated by proteasome dysfunctions. In the livers of mouse models of obesity, proteasome activity is reduced and polyubiquinated proteins accumulate. In these mice, impaired proteasome function leads to hepatic steatosis, hepatic insulin resistance, and unfolded protein response activation. Treatment with chemical chaperones partially reverted this phenotype.
Unity Biotech changing paths from senolytics to "messin' with metabolism"??
https://finance.yahoo.com/news/unity-biotechnology-inc-ucsf-enter-200500046.html
Hi there! Just a 2 cents.
Yes, obesity definitely speeds up the aging process (on the morbidly obese level), mildy-obese/chubby may not do so. Studies have been conflictual about 'how much' is that obesity (in terms of pounds per inch); not one body is the same, one thing may work in one and not so much in another. It's why CR can sometimes backfire (depending on the state of person (obese vs anorexic vs thin vs normal-size, healthy vs unhealthy/frail), that person may be obese but healthily-speaking is above threshold for health compromising. It's over time that the low threshold may be reached and then obesity will causes diseases progression. We also have to remember that someone may be heavier but that is due to more skeletal muscular mass or BMD (bone mineral density/thicker hollowless bones or 'wider hip/shoulder/larger' skeleton), and not due to increase visceral fatty mass around organs (which, the latter, is, oftenly, the case in obese people). I have seen obese/borderline people live long lives, mostly healthy...never got what I got (athersclerosis), I was never obese/ever...always below 150lbs..for 5'10. Goes to show that what happens 'inside' can happen in a fat body or a thin body...no matter; the visceral fat can accumulate in thin people or obese ones...no difference; making 'thin' people have 'obese' diseases, like I had.
Studies are also conflictual about which one is better; some studies showed that certain birds that were ad libitum fed/go eat whatever...did grow bigger and had - Taller - telomeres, not shorter (the CR birds were frail and had smaller telomeres, demonstrating the danger of overt CR causing loss of fitness by undernutrition malnourishment)...demonstrating that nutrient (IGF/IR/DAF/SIR/mTOR) is at crossroad, to telomere preservation; but Overnutrient = mTOR hyperactivation = increase fitness but at cost of IGF/insulin hyperactivation = skeletal glucose disposal/WBGD (whole body glucose disposal) dysfucntion...in other words, diabetes or pre-diabetes as the pancreas'beta cells are taxed in insulin production to maintain blood normo-glucose levels. Diabetes is also causal to atherosclerosis because it increases triglycerids, fatty, LDL cholesterol depots in arterial lesions.
I think the most telling element is the epigenetic element; that is a Clear demonstration of accelerated aging by obesity - or - frailty (frailty that compromises not frailty that 'can be survived', meaning, you can be frail - and survive it (just like oxidative stress resistance; or, you can die of it if you succomb to it)...either one.
Obesity, because, they show at least 2.7-3 years acceleration of aging...and it's intriguing because it demonstrates that the faster the methylome is demethylated the faster the epigenetic signature advances (clock tabs adding up, later will create replicative senescence entry). CR is capable of extending the lifespan of animals (and it's interesting that tehy say that the Thin mice that did CR saw no lifespan increase; showing that keeping a low-to-moderate BMI is crucial to get maximal lifespan; demonstrating that the thin mice were already at 'CR'-like values by keeping thin shape - and they saw no lifespan extension. Meaning CR itself retards the epigenetic program advancement (or in this case, keeping a low BMI/thin like the thin mice), and why, CR extends the lifespan of animals. CR was shown to reduce loss of histones and methyls in the methylome, proving that is slows aging, plus CR also maintained telomeres - with that said, *Overt CR (severe famine/starvation/ultra-long fasting/undernutrition) does the inverse, causing frailty/loss of fitness and acceleration of aging/telomere loss), people can become hypoglycemic on CR, causing coma/brain dizzyness because no carbs in blood towards brain (a carbs-richh and cholesterol-rich consuming organ). Not one person reacts the same, for some, they can do fasting/water-fasting for weeks and seem like nothing; they accustomed body to starvation....I don't recommend that unless you know what you are doing (to you/your body/listen to it), because dangerous.
CR is a Stress. Undernutrition stress (abrogation of mTOR). Obesity is a Stress. Overnutrition stress (hyperactivation of mTOR). Between telomeres and DNA epigenetic aging, both are determinants of aging; but, epigenome is more accurate measure. Telomeres can see 'sudden changes' that may not mean much...while epigenetic changes are 'long before' and 'predict' waht's coming. At the bottom of it (literally, and, figuratively), at the bottom of the telomeres and the dNA epymethylome you lose them; and whne you lose them, that is how aging happens. Telomeres shrink and global DNA methylation levels drop (we lose 50 bp/year (DNA base pairs nucleotides) in telomeres (while HGPS progeric premature aging people lose 500 bp/year (and live only 15 years), and, lose 1% of 5-metC per year in methylome; studies showed the immortal cell lines never go below 2kb telomeres and never lose complete 5-metC levels (in fact, unlike humans' normal cells that lose it each division, immmortalized cells' content keeps on rising each division); showing that for infinite proliferation you cannot keep on 'losing DNA'...it's death, assured, later; because, it means the activation of Many deleterious genes and the 'program' of aging/death (inflammatory genes activation contributing to that)). Increasing telomeres like Mrs. Bioviva herself Mrs. Parrish is a possible helper (yet there is still ambiguity about it; for some studies said that increasing teloemres means advancement of DNA epiclock...which is possible if ambiguous; overall there is far more litterature for keeping telomeres taller; CR keeps telomeres taller, that's a sign...yes, longer telomeres, may mean more mutations and possible 'cancer/stem-cell like activity...or, I would call it' 'Overjuvenility'/'Overneotenous' capability... which means your body is Very active in terms of cell proliferation/division which may cause higher load mutations with age; and why, the body 'protects itself' from too many mutations with age - By Aging You....it's a negative feedback mechanism - just like curbing cancer (seen as shortening telomeres/replicative breaks).
One more study showed that CR though did increase sexual capability over long-term by reducing inflammation/SASP/oxidative stress; mostly, in short term it induces sexual dysfunction/senescence because it is relocation of 'resources' (by nutrients); since there is undernutrition (starvation), the body compensates by 'taking away' the sexual resources - for somatic cell tissue maintenance; this is why you see reduction of 'offspring/progeny' output during periods of famine. There is inabundance, thus, the body can't even produce sexual output (need resources for that - from nutrients). We can see gonadal/sexual organ tissue shrinking/amorphism in CR. mTOR = sexual capacity/fitness = nutrients.
CR = no nutrients = no sexual output/reproduction = relocating 'psarse nutrient' resources towards longevity/own tissue. Obesity = overnutrtion = mTOR activation = triglyceride formation/fat depot/LDL = skeletal muscular insulin dysfucntion = diabetes/atheroslcerosis. On epigenetic level, you even see, loss of telomere and methyl count; demonstrating True aging. IT is the samw thing as Cancer...cancer shows True aging (cancer patients lost more global methyls and have hyper methylation of Specific methyl locus (the ones that cause inflammation and the ones that 'fight cancer' (TNF, p53, tumor suppressors...which contribute to cancer immunity but also, senescence, for they are inflammatory and cause massive ROS production to destroy the cancers).
In the end, yes, obesity is far more a problem than being thin is...but both can be problematic and you can die thin too. It's far more complex that simple obese/thin; there is Many nuances in the body; which can show you 'outliers' - people are who Very fat/obese and Do Not die of anything...yet, other people, who are thin in perfect health - die suddenly. I read about a man who was 36 years old (lil bit younger than me) was in perfect health (or so we thought), ate vegeetables no junk no stress...did exercice...did everythign right...one day goes to exercice for daily routine and, dies suddenly while walking.
Such is life.
Just a 2 cents.
PS: Obesity is a serious problem and most be considered as a major concern for people who suffer of that; because, from the clock, they really are aging a (bit) faster...all these nutrients cause hyperactiavtion of mTOR geroconverter to senescence..it's like that - nature does not want us adlibitum resources - it wants us to 'share/take in just waht we need'...not glut in it because others need them too ('when you go drink water at the fountain...leave some for the fishes').
PPS: One study recently showed that thin or very thin (near anorexic) people had much higher odds of sudden death than obese people; because, of frailty...obesity...though bad...is good for giving you at least some 'strength'/a 'body'...so you don't crack....though too much of it. Older people saw an advantage of obesity, the metabolism slows down...not thin anymore - they don,t burn fat anymore - so they accumulate belly fat and become obese in their 50-70s...and it's actually 'midly' protective...because of frailty/'mild' fitness effect...meaning it paradoxically protects them by simply affording them a 'body' to begin with..while a thin person/anorexic person is too compromised to function over long term (undernutrition is more dangerous on 'health maintenance' than overnutrition) - hence, dying of frailty by overt thinness/anorexism. With that said, do you see many obese people reach 120 years old...it's rare than rare; albeit..certain people that show obesity in 60-70s...may end up reacing 100 years old for they are already 'reached that late point'...and can sustain function even so; the diseases are not drastic enough to compromise health (excess frailty). I would not surprised seeing a study showing that some centenarians were in fact - at one time - not so thin or had some chubbyness/border obese for a short bout of time in 40-70s decades..and it was ok...even, paradoxically, helpful - for maintenance of health threshold (not go into frailty/undernutrition). They - later- got back their shape and lost the extra fat; the negative effect was mostly negated...
but, the inverse, being anorexic is far more ravaging and cause fragility/bruising/frailty/diseases/ sudden death. Maintaning health = Need nutrient for that.
PPPS: One Russian study showed that mutations/errors are the cause of aging; accumulating ni epigenome; mouse and gerbils were accumulating 4-6x10-4 mutations ; while humans were accumulating 2-3x10-6; humans might accumulate more mutations but they are rendered futile; while in shorter lifespan animals they are more consequential, even in smaller numbers (simply because they can't 'overcome' them, unlike the more fine-tuned human cells). And there was a clear correlation between epigenetic drifting, loss of epistasis, loss of methylation, and accumulation of these mutations 'errors' in DNA; such as T/C to U mutations (thymine/cytosine to Uracil/uric acid nucleotide exchanges..causing widespread dysfunction and advancing the aging program). Same thing for telomeres, TAGG (thymine adenine guanine) being wiped or changed for some mixture that creates overal genomic dysfunction/epistasis loss=advancement of epiclock.