Calorie Restriction Slows the Age-Related Accumulation of DNA Damage, Inflammation, and Cellular Senescence in Fat Tissue

The practice of calorie restriction slows near all measures of aging, slowing aging to a degree that appears to scale down with increased species life span. Calorie restricted mice live 40% longer, but calorie restricted humans are thought to at most gain five years or so - though a firm number has yet to be determined in our species. The short term changes to metabolism and benefits to health are nonetheless quite similar. As a companion piece to recent work on the effects of calorie restriction on cellular senescence, this open access paper makes for interesting reading. Senescent cells accumulate with age, and the damage they do to their environment via a potent mix of signal molecules is one of the root causes of aging and age-related disease. Unsurprisingly, calorie restriction slows this accumulation, just as it impacts all other processes of aging.

White adipose tissue (WAT) forms an endocrine organ with both positive and negative effects on metabolism. By secreting adipokines, adipocytes regulate metabolism, energy intake, and fat storage. Adipocytes are known to enlarge during obesity and the ageing process. In contrast, caloric restriction results in decreased body mass, and preferentially reduced the mass of different fat depots including up to 78% in visceral fat. Several studies demonstrated that increased fat cell size is a significant predictor of altered blood lipid profiles and glucose-insulin homeostasis. The contribution of visceral adiposity to these associations seems to be of particular importance.

Senescence and inflammation are two important mechanisms contributing to ageing and the metabolic consequences of obesity. Inflammation can result from accumulation of macrophages in adipose tissue via production of cytokines such as TNFα and IL-6. Increase in lipolysis has been shown to induce macrophage migration in vitro. Macrophage numbers in adipose tissue also increase with obesity and ageing where they scavenge dead or senescent adipocytes. However, inflammatory cytokines and chemokines are also characteristics of the senescence-associated secretory phenotype (SASP) in senescent cells. We have shown previously that reactive oxygen species (ROS), DNA damage, and mitochondrial dysfunction are instrumental to maintain cellular senescence.

Various treatments have been suggested to delay senescence in adipose tissues while obesity and short telomeres exacerbated senescence. A recent study showed that feeding a high-fat diet ad libitum induced senescence in mouse visceral adipose tissue which could be ameliorated by exercise. However, dietary restriction (DR) seems to regulate many more genes than exercise in subcutaneous fat in humans.

We have demonstrated previously that short-term dietary restriction in wild type mice decreased the amount of senescent cells in various tissues. We hypothesise that pro-inflammatory cytokines and senescence are also causally related in visceral WAT, increase together during ageing, and might be rescued during DR. We used visceral WAT from mice of different ages as well as mice on late-onset, short term DR to investigate the changes in adipocyte size, accumulation of DNA damage during ageing and DR, together with the expression of pro-inflammatory cytokines TNFα, IL-6, IL-1β, and senescence markers p16 and p21. We also analysed AMPK activity which is an important signal transduction pathway implicated in the regulation of physiological processes of DR. AMPK activation is thought to be able to inhibit inflammatory responses and plays a central role in the regulation of whole body energy homeostasis and functions as a key regulator of intracellular fatty acid metabolism.

Our results demonstrate increased senescence and inflammation during ageing in mouse visceral fat while DR was able to ameliorate several of these parameters. DR was able to significantly reduce adipocyte size and multiple markers of adipocyte senescence (significant for DNA damage, p21 and IL-6 expression). This indicates that DR acts as a senolytic treatment in visceral fat, similar to its effects in other tissues. This highlights the health benefits of a decreased nutritional intake over a relatively short period of time at middle age.

Link: https://doi.org/10.1007/s12603-017-0968-2

Comments

Now we need a correct protocol of DR,CR or outright fasting. Intuitively, it seems that CR can stimulate the autophagy, which can prevent pre-senescsant cells beginning senescent and even killing some weaker cells who don't have get enough energy. On the other hand the human body is easy to complex and the there might be some negative effects too. That's why a correct portfolio is so needed

Posted by: Cuberat at April 5th, 2018 6:12 AM

I've fasted four times using the Prolon diet over the last 15 months. After each fast I've lost about 1/4" on my waist, and it hasn't come back, even after returning to my normal diet.

I don't have any quotes, but I have read somewhere where Valter Longo states that fasting-mimicking diets of five days do clear out stubborn body fat that accumulates with age. Maybe the stomach fat cells perform apoptosis?

Posted by: DdR at April 5th, 2018 9:03 AM

Genetically, it would be more beneficial for you if you are homozygous for the good alleles of TNF-a, IL-6, IL-1b, and AMPK genes. I checked my genome and am homozygous for the beneficial SNP allele of all 4 of these genes.

Posted by: Biotechy at April 5th, 2018 1:20 PM

About 10 ago I did a 22 day fast and lost closer to 50 pounds. And ate the fading was getting great. But I was young and going from obese to moderately overweight helped a lot. But did this fasting clean some bad cells and cross links? Or did it actually made my bode worse off?I dunno...

Posted by: Cuberat at April 5th, 2018 2:11 PM

I am always interested in strategies for lifestyle improvement and augmentation, but this search is always subject to assessing the 'quality-of-life vs quantity-of-life' non-false (IMO) dichotomy. I am not averse to managing my calorie intake however, this:
"...
Undernutrition without malnutrition is an intervention that enhances laboratory animal life span, and is widely studied to uncover factors limiting longevity. In a search of the literature over a course of four years, we found that most protocols currently adopted as caloric restriction do not meet micronutrient standards set by the National Research Council for laboratory rats and mice. We provide evidence that the most commonly adopted caloric restriction protocol, a 40% restriction of the AIN-93 diet without vitamin or mineral supplementation, leads to malnutrition in both mice and rats. Furthermore, others and we find that every other day feeding, another dietary intervention often referred to as caloric restriction, does not limit the total amount of calories consumed. Altogether, we propose that the term "caloric restriction" should be used specifically to describe diets that decrease calorie intake but not micronutrient availability, and that protocols adopted should be described in detail in order to allow for comparisons and better understanding of the effects of these diets.
..."
Of course I am extending my inquiry (and especially my scepticism) specifically to human beings. As a counter balance, there is this:
"...In nonobese adults, CR had some positive effects and no negative effects on health-related QOL. [...Compared with the AL group, the CR group had significantly improved mood ..., reduced tension ..., and improved general health ..., and sexual drive and relationship ...at month 24 as well as improved sleep duration at month 12
..."
It is certainly not simple to find the 6-month daily plan of nutrition and acceptable activities that meet CR, in a non-clinical setting, assuming traditional lifestyles commitments (50-hr work weeks, demanding spouse and dependents, and desire for wide variety of tasty and accessible consumption options). Ask me not to decide/ contribute/ advocate between living to 150 without these things vs living to 75 + 10yrs decline with these things, since the 'without' will never win such a lifestyle choice.

Posted by: Jer at April 7th, 2018 8:54 AM

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