Calorie Restriction Suppresses the Senescence-Associated Secretory Phenotype

The accumulation of senescent cells is one of the causes of aging, important in the chronic inflammation of aging, and disruptive of tissue structure and function. The practice of calorie restriction slows the progression of aging, much more so in short-lived animals than in long-lived species, and thus we should expect it to have some effect on cellular senescence. Calorie restriction is nowhere near as effective as senolytic drugs at reducing the populations of senescent cells present in older individuals, that much is evident from studies carried out in recent years. As noted here, however, it does appear to somewhat reduce the inflammatory signaling generated by senescent cells.

Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view.

Senescent cells produce a proinflammatory senescence-associated (SA) secretome, which is referred to as the SASP. Macrophages are recruited by chemotactic factors in the secretome to clear senescent cells. However, senescent macrophages secrete proinflammatory cytokines and exhibit impaired phagocytosis and chemotaxis, and a downregulated rate of cellular proliferation. It has been proposed that deficiency in the ability of aged macrophages to clear senescent cells leads to increased inflammatory response and results in chronic inflammation as SASP plays a role in the initiation of tissue inflammation. Based on previous observations and evidence of the aging process at molecular and cellular levels, we coined the term senoinflammation to provide an expanded, broader view of age-related chronic inflammation and metabolic dysfunction.

Based on studies on senoinflammation and CR, we recognized that the senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. Oxidative stress leads to improper gene regulation and genomic DNA damage during aging. Such improper gene regulation in aged senescent cells allows them to fall into a proinflammatory state, consequently changing systemic chemokine or cytokine activities. The proinflammatory SASP environment further exerts stress on the intracellular organelles, tissues, and systems, which affects the development and occurrence of metabolic disorders.

It appears that a repetitive vicious cycle occurs between SASP and metabolic dysregulation as proposed in the concept of senoinflammation, and this interactive network forms the basis of the aging process and age-related diseases. However, the secretion of proinflammatory mediators, collectively termed as SASP, in response to internal and external stress leads to the chronic inflammatory condition termed as senoinflammation. Based on CR experiments and observations, cytokine, chemokine, and metabolic pathways are significantly regulated by CR and CR mimetics in the aging process.



It has been known for a long time that calorie restriction suppresses inflammation. Probably due to enhanced mitophagy and reduced oxidative stress. That alone could help some marginal SnC to repair and reduce the rate of forming of new ones.

The calorie restriction mimetics here show surprisingly good effect. Probably due to impaired mitophagy in first place. One interesting question is can calorie restriction and fasting be enhanced by CR mimetics like metformin, rapamicin, flavonoids and friends. And how big that enhancment would be...

Posted by: Cuberat at February 27th, 2020 7:36 AM

Hi Cuberat! Just a 2 cents.

I believe they are mostly acting in the same (redundant) pathways as such, the synergical effects are lesser and lesser as you add up, it is not 'synergical/multiplying/combining/additional' effect like that, much more redundance thus nothing much added; it's a bit the 'one calorie mimetic replaces/does same/nearly same as 1000 calorie mimetics - no or little more difference'. It's the 'Moore's Law' of 'Diminishing Returns' with (more&more) CR mimetics taken and basically, any therapy so far - in mouse - translated to human - is diminished return. By acting in the same pathways, redundancy happens. Can't get anymore benefit if pathway used already, this happened in Many many studies relating to CR stuff (SIR/DAF/FOXO/IGF..) once you do the pathways, it ends there, it's not because Another CR mimetic goes for it that suddenly 1 more changes anything; it's the Pathway that gives the benefits. You can only 'call it/use it' so many times by so many 'askers'/CR mimetics, until it is redundant once more.

I agree though that increase mitophagy/autophagy, via CR mimetic, is very important/good and will greatly help stave off residue/Junk accumulation of aging. But, you can already do that, just taking a hot shower or doing exercise - which all activate autophagy in some way; because autophagy is backup/failsafe system to clean up gunk/deadmito/DNA Junk cumulating and it activates during 'stress'; stress, oxidative stress Strongly activates autophagy 'as a response' to 'remove all the Junk you are creating during that stress'. ROS during ox. stress directly activates/preps autophagy because there is immediate accumulating of all these residues - that need to 'be taken out' like garbage (through the lysosomes to consume them/degrade/phage them).

CR is now become more niche, it's still very talked of and important as Something for health and longer lifespan; but, in the eyes of 99% of longevity people/investors it is only making money because 'sell CR supplements'; but, 'Longevity/Time' is not really Something it's giving; thus, there is Also diminshing returns on CR - both to you and on your money. (It's people are connecting the dots and realizing they will still die, cr or not, so must use money resource towards Something else that Really, Does stop aging/end aging - I love the sound of that. END aging. And saying it with a straight/serious face in front of your family who took you are a martian comic thinking we can defeat aging; End aging. More seriously, End death/Cure death).
Sadly, Eternal life possibility is still thought as a big joke and if were possible people spit on it when given on a silver plater free (because Eternal life is too long/boring/too ethically uncorrect/unnatural/and everytoher reason possible (for them that is)), I hope that in my lifetime I get to see it happening and get to tell them 'I Told You' (if they are still alive and have changed mind and decided it's not bs fiction anymore (some said - 'Watch them - they will be 'lining' one behind the other with their Hands Open - Begging for it and saying 'sorry we never thought it could Ever be possible and now, no, we don't want to die anymore'/seen enough people dying as it is so Eternal life, we'll take it/ride it as long as we can).

Just a 2 cents.

Posted by: CANanonymity at February 27th, 2020 4:28 PM

CANanonymity...In a world about to be thrown within the next century into resource wars, famine, starvation, drought, weather emergencies, how wrong it is for humanity to begin living forever on this earth? I can cope with longer lifetimes; but how long will be "too long", when people are filling every little 3x3-foot corner of the earth? How will we feed the world? And when automation comes full-force, how will people work and earn money for food with so many competing for the few jobs that still need to be done by humans? Humans should be able to certainly age better and have better functionality and quality of life until their moment of death; and perhaps the moment of death could be later than it is, now, but not by 100% or more. This world is already staggering under the weight of the environmental abuse it's receiving. The Amazon is being deforested rapidly, glaciers on the poles of the earth are melting, coral reefs are dying, animal migration patterns are shifting such that birds are moving north earlier in the spring before their needed specific foods are ready for them, the oceans are being polluted. We really do have to solve these problems and more before we have humans extending their lifespans by 100% or more.

Posted by: Antonia at March 1st, 2020 1:53 PM
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