Sarcopenia as an Inflammatory Condition, Driven in Part by Cellular Senescence
Sarcopenia is the name given to the characteristic loss of muscle mass and strength that occurs with age, though insofar as the slow progress towards an official clinical definition is concerned, this only counts in the more advanced stages. We could do with less of that sort of thinking in medicine and research, as all age-related declines are a problem, and the earlier they can be addressed, the better. If a therapy addresses the root causes of an age-related condition, then it should be just as usefully applied every so often starting at 40, as a preventative treatment, as it would be starting at 70, in order to turn back much larger amounts of damage.
Sarcopenia is a great example of the way in which many areas of research into aging resemble the parable of the blind men and the elephant; every specialized research group looking at just one layer in a complex, interacting set of mechanisms and outcomes, and claiming their layer to be the most important. When reading the literature on sarcopenia, there are many theories and causes, most of which are backed by good evidence. Think of disruption of regenerative processes via chronic inflammation and stem cell decline, the role of cellular senescence in achieving that disruption, or, separately, neurological decline in the links between muscle and nervous system, reduced protein intake and lack of exercise in older individuals, and an age-related failure to process dietary amino acids.
As things stand, I think the stem cell researchers have a compelling last word with regard to the size of the contribution of declining stem cell activity on muscle atrophy in aging versus other possible causes. We then have to ask, however, why does muscle stem cell activity falter with age? What are the mechanisms driving that change? Research in recent years points to inflammatory signals as one of the ways in which regeneration and tissue maintenance are disrupted, and some portion of that inflammation arises from the signaling generated by growing numbers of senescent cells. Still, each of these named items is just one layer in a complex system - a system that is too complex to model well today. There are plenty of other causes of stem cell decline with evidence to support them. The true size of any specific contribution, the importance of any specific connection, will only be determined in the near future through some form of therapy that removes it. The best and fastest way to understand aging in detail is to fix the known forms of damage, one by one, and observe the results.
The paper here considers inflammation in sarcopenia, but not from the perspective of stem cell tissue maintenance. Rather, the authors focus on the way in which age-related increases in chronic inflammation might interfere with the protein synthesis needed to build muscle - which comes back around to the various studies suggesting that disruption in the processing of nutrients is a contributing cause of sarcopenia. Eventually everything is connected to everything else in aging and cellular biochemistry, given enough time to find the links. Advances in senolytic therapies to clear senescent cells and their inflammatory signaling, coupled with ways to reverse the age-related dysfunction of the immune system should in years ahead help to determine the degree to which sarcopenia is caused by inflammation.
The Role of Inflammation in Age-Related Sarcopenia
One of the major problems in the aging population is a progressive loss in skeletal muscle mass, muscle strength, and/or functionality, described as age-related sarcopenia. Several strategies to attenuate the loss of muscle mass and other muscle impairments that comes with aging have been developed. However, none of these have been proven successful to fully reverse the muscle wasting condition. Given the high prevalence of sarcopenia in the aging population and the associated high health care costs, it is of importance to reveal and elucidate the working mechanisms which underlie muscle protein metabolism in the elderly, in order to optimize the classic interventions and/or to develop new ones.
Muscle protein metabolism is carefully regulated by counterbalanced fluctuations in muscle protein breakdown (MPB) and muscle protein synthesis (MPS). In the elderly, the balance between MPB and MPS seems to be disturbed, which progressively increases the loss of skeletal muscle mass. Many underlying factors such as hormonal changes, decreased activity, diminished nutrient intake, and neuronal changes were reported in the literature, but lately, the role of inflammation on the regulation of muscle protein metabolism has gained more and more interest among gerontologists.
Generally, aging is associated with a chronic state of slightly increased plasma levels of pro-inflammatory mediators, such as tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and C-reactive protein (CRP). This state is often referred to as a low-grade inflammation (LGI) and is, at least partly, the manifestation of increased numbers of cells leaving the cell cycle and entering the state of cellular senescence. Indeed, senescent cells acquire a Senescence-Associated Secretory Phenotype, which induces the production of pro-inflammatory cytokines (TNFα, IL-6 and an overactivation of NF-κB). Moreover, there is a growing interest in the association between the telomere/telomerase system and LGI, as cellular senescence can be triggered by critically short telomeres, representing irreparable DNA damage. Also, there are indications that LGI can directly cause telomere/telomerase dysfunction, enforcing the vicious LGI circle and stimulating an accelerated aging phenotype.
Although it has been suggested that inflammatory mediators affect muscle protein metabolism, it is not fully understood to what extent and through which signaling pathways they induce muscle wasting. Population-based data suggest that circulating concentrations of IL-6 and TNFα are significantly elevated in sarcopenic elderly and it was reported that higher IL-6 and CRP levels increase the risk of muscle strength loss. In a 10-year longitudinal study in community-dwelling elderly, plasma concentrations of TNFα, IL-6, and IL-1 were shown to be strong predictors of morbidity and mortality in older subjects. Furthermore, systemic inflammation was also reported as one of the primary mediators of skeletal muscle wasting and it was shown to accelerate aging in general. Without pronouncing on causality, these findings suggest that there is a link between inflammatory mediators and muscle mass and function.
A number of mechanisms have been shown to contribute to the etiology and/or progression of muscle wasting with advancing age. Somehow, many of these mechanisms interfere with inflammatory mediators. However, further research is required to determine through which mechanisms inflammation directly or indirectly affects MPB and MPS with aging. Classic interventions such as protein supplementation and resistance exercise are generally accepted to be the most appropriate to positively affect muscle protein metabolism in elderly. However, not all studies univocally support the effectiveness of these strategies for long-term treatment of age-related muscle wasting. Elderly, and very old or frail seniors in particular, might benefit from a strategy primarily focused on alleviating their muscle insensitivity to anabolic stimuli. In this regard, the treatment of LGI in these elderly might play an important role.
Centenarians are known to have relatively low levels of inflammation that are implicated in muscle wasting in the elderly. You want to have good genetics for the TNFa, IL-6, IL-1a, IL-1b, CRP genes, with the longevity producing alleles for as many of these genes as possible. Examples of the most beneficial SNP alleles for TNFa SNP's are rs1800629 GG, rs361525 GG, for IL-1a SNP rs16944 GG, IL-1b SNP rs1143634 GG, IL-6 SNP rs1800795 CC, and for CRP SNP rs1205 CC. Having these gene SNP alleles will greatly minimize your inflammatory risk. Also, you want to have healthy muscle mitochondria, and that means you want to have the most beneficial genes and SNP alleles that will reduce muscle wasting during aging. Among the most beneficial gene SNP alleles to have are SIRT3 rs28365027 GG, UCP2 rs659366 GG, and UCP3 rs1800849 AA. The last UCP3 listed here has the best grip strength in Danish Centenarians, which is the best measure for muscle wasting.
I'm just a layman but very interested in Fight Aging! and the SENS approach. However, regarding Sarcopenia I would rather go with this explanation (taken from Wikipedia) for its cause:
"One group has suggested that the evolutionary basis for the failure of the body to maintain muscle mass and function with age is that the genes governing these traits were selected in a Late Paleolithic environment in which there was a very high level of obligatory muscular effort, and that these genetic parameters are therefore ill-matched to a modern lifestyle characterized by high levels of lifelong sedentary behavior."
Even in my sixties I could easily combat and reverse the signs of muscle mass and strength loss by doing resistance exercise.
The genetic results I posted above are from various genome research papers that are referenced under the respective SNP number in SNPedia which you will need to Google if you want to see all the recent genomic study info you will want to go there. Incidently, I am homozygous for all the beneficial alleles of the SNP's I listed accept the UPCP2 SNP, for which I am heterozygous for the good allele. Perhaps in the future you can get the beneficial alleles with CRISPR technology, if you didn't inherit them.
Hey Bardu!
Welcome to the hub! It takes a while to get used to the ins and outs of biotech, but this site is VERY educational and encourages you to learn a bit about genetics, biotech, regulation etc. Good way to keep the brain in good shape for the next few years until we have some solid tech :)
@Mark Borbely
I'm following Fight Aging! already for years, basically after reading Ending Aging from Aubrey de Grey. I have to admit I didn't understand much of what I was reading. This blog and others have helped me to get more insides and better understanding.
However, I have more practical interest. I want to live as long as possible in the best health. And I'm doing a lot for it from a lifestyle perspective. I'm on Paleo diet, do CR, daily outdoor and/or gym exercise, fasting. And it doesn't hurt me; I'm enjoying it.
My understanding is that research hasn't much better things to offer yet proven in clinical trials to extend human lifespan. That is no offense I acknowledge that lack of funding and the FDA are major roadblocks.
@bardu
There are actually some things to offer. Quite a bunch of self-experimentators at longecity forum done Dasatinib + Quercetin as antisenolitic treatment. Now they have done a group buy of a FOXO4-DRI peptide with the same goal.
Even more promising, from my perspective anyway, nicotinamide riboside opened a door for new ideas about manipulating mitochondrial quality control, that could be the key to addressing underlying cause of aging
Did anyone on longecity or the fightaging community participate in the FOXO4-DRI group buy and get a skin biopsy? I think I saw a skin biospy suggested by Reason somewhere as the only real measure of whether there is any effect?
If no one is getting a skin biopsy, maybe I should buy some FOXO4-DRI and get a biopsy. I don't really know where to begin on getting the biopsy though?
@Andey
Thanks for that information. I take Quercetin as well but only at the end of fasting as suggested here:
https://joshmitteldorf.scienceblog.com/2017/04/07/is-fasting-senolytic
Have the self-experimentators at longecity forum shared any outcome of their tests?
Ok here is FA's article on skin biopsys for testing levels of senescent cells, it doesn't look like I could practically get this done at present.
https://www.fightaging.org/archives/2017/05/the-basis-for-a-skin-sample-test-of-level-of-cellular-senescence/
@bardu
I believe 2 people wrote positive effect on cardiovascular system - like high blood pressure returned to normal permanently after a month or two post-treatment. There is a trend that the more advanced age somebody is, the more profound flu symptoms are.
From this pair dasatinib is more important one, I don't think quercetin would do anything major by itself.
Longecity is a difficult demographic for obtaining measurable results, most people are middle age so there is nothing particularly wrong with their tests, to begin with. And frankly, 99% don't bother with tests, etc.
@Jim: The currently available skin biopsy method would be staining for SA-beta-gal, just like they do in lab rats, which would be custom lab work, but could be done. However, I think that the work needs to be done to validate that this is in any way useful in a biopsy versus sacrifice situation, since senescence occurs in response to wounding. It is possible that the transient senescence will mess up any naive attempt to use biopsies to test senolytics.
@Reason
Is it sensible to use the level of IL6 as a proxy for SASP phenotype representation?
Like, measure it before intervention and one month after. Or is it too volatile for this purpose?
@Andey: I'm not sure. The SASP consists of a ridiculous number of molecules, and the research community is still hacking through the mess to figure out which are more or less relevant. I think the details will turn out to matter greatly when it comes to trying to figure out a decent metric. There are a bunch of papers on characterizing SASP, most written from a fairly narrow point of view of how SASP influences some other particular small area of cellular biochemistry, and they tend to focus down on a few better known molecules. But that doesn't mean those will be useful to measure.
I don't think that your question is going to get answered soon, short of researchers running a characterization of various levels of various things before and after a senolytic treatment shown by other ways to clear cells.
So if we can't reliably measure things before and after an intervention how can we tell the success or failure of this intervention?
I don't want to sound negative I'm always optimistic. However, a gym buddy of mine who is 70, and still, a practicing surgeon answered my question about human lifespan like this: "To my experience, it is all about luck."
@bardu: See this for discussion on measurement: https://www.fightaging.org/archives/2018/01/how-to-plan-and-carry-out-a-simple-self-experiment-a-single-person-trial-of-chemotherapeutic-senolytic-drug-candidates/
@bardu:
anyone can come up with a shallow short answer to lifespan possibilities, but it should be a science-based if at all possible. Like how many centenarians do you have in your family tree. What longevity genes do you have. At a minimum, you should know what your FOXO3A longevity SNP's are, and APOE SNP status. If you have raw DNA data from one of the genomic companies like 23andme, Veritas, results from Promethease, you can figure out what your major genetic health risks are and work on your lifestyle, diet, exercise regime, sleep pattern to optimize your health span until something better comes along fro SENS, etc.
@Biotechy:
Well, if someone with more than 40 years of experience as a surgeon gives me such a quote I wouldn't consider this a shallow short answer.
Well, if you are willing to swallow that answer with no further curiosity, go with it. However, lifespan statisticians can give you more detailed info, so can the numerous genome research articles out there and the genetic services ready to help you. Your immediate family ancestry is a good starting point to see where you fit on the bell curve. If you have no centenarians in your ancestry, figure out how many made 90 or 95 and work out the statistics and try to apply it to yourself. I happen to have 6 centenarians in my family, and 23 who lived to 90 or more. Being 77 already, Gov. statistics say I have about 50% chance of making 90 already, though I am planning on the 100 plus and if I make 107 I will be the oldest in my family tree, unless some of my cousins get there first.
Biotechy, you are lucky. Unfortunately, I don't have these genetic traits in my family tree. When I lived in the bush I met a couple, which became good friends, both of them had a similar family history as yours. Most of them made it to their late 80ties and 90ties. He passed away suddenly at dinner when he was 86, she left us a year ago at the age of 93.
What confuses me is that some research paper claim life expectancy is all about someone's lifestyle and up to 20% genetics and some claim the opposite.
BTW, I didn't swallow the answer of my friend, even it was devastating for a moment. That's why I'm here.
Hi there ! Just a 2 cent,
I believe that it is about equal, 50% lifestyle (diet, exercice, suppl. etc/environment/stress)
and 50% inherited genetics.
I say this because oftenly Both have been either Overweighted or Underweighted. Things like 80% lifestyle and 20% genetics is complete bunk. Likewise, 80% genetics and 20% lifestyle is too.
Why... because there are centenarians (outliers) whom lived to 105-109 years old doing most of everything that kills you. Yet, there are other centanarians whom did The Inverse, and did all the right things, and lived to 105-109 years old TOO. This means that lifestyle factor is in fact not so strong after all. Not for Long Term at least, in the short term yes; but for very long term:
You could Very Well be gifted with A Genetic that protects you from Things That Kill Others.
So you can not simply say 'down to lifestyle/diet'..why do certain people do these diets and such; and see little benefit and other big benefit; it means there is no one size fits all and not one person shares the same; each body responds differently to insults/aging/lifestyle changes depending of their inherited birth genetic makeup. Plus, certain people are more frail than others or their health state can change more, for the worse.
When you ahve many centenarians in your family, it is a safe bet that you have More chances on your side of making it, than not. IF you don'T have any, it's going to be tougher; but it is not the end either, for there are Lucky few ones whom are Really outliers in their own family. Like 'That' odd 1 centenarian whom lived to 101 and everyone else in the family died at 60-80.... why this 1 person, must be Something else, maybe their lifestyle, they drank the magic elixir who knows. This is akin to J.Calment, she lived to 122, but no one else in her family lived that long (albeit she did have long lived brother and thus, she had a strong genetic component to Why she lived 122; it was not just 'diet/olive oïl/porto wine/chees/chocolate'...cause thousands others feasted on these and Never Ever reached 110-120 either).
I say genetics, because, if these Survivor centenarians do things that kill others, but still reach 110 years old; it means the genetics are generally Underweighted to their weight in the balance. That is why you can see these extremely long-lived people eat stuff that kills anyone that does not have 'centenarian genes SNPs à la FOXO SIRT DAF'. Why do they not die, while others do. Genetics, protective and makes the consequences lesser in them; or not enough to them die of it at least. When you have better genetics/less compromised and special SNPs, it helps a lot getting that extra-mileage and protects you from insults (That kill others who do not have these gene perks from birth. When you have it for life since your birth; well you have been 'shielded' for a long time, it helped).
They say the genetic component is more and more important as you age; in the late years, 60, 70, 80 years old the genetic component is at its highest because it is deterministic as to you will live to 80-90 or you will get to 110. lifesstyle at this late point offers weaken effect and not really impacful. In your younger years, lifestyle chages can dramatically alter 'the later' course of your life (the 2nd part 60-100 years old). Thus, when you are Young, you still have a chance to 'somewhat' alter the trajectory but even then at this early time, genetic is also important just as it is From the Very Birth. Many studies showed that Early Life effects had deep impact Later On in life; thus early genetics impact it too (at birth espeically where things decided themselves when you inherited from parents); and then in mid-life, it's your time to 'change' the trajectory (Change diet, exercice etc...) to try to mitigate the late end part coming too soon.
Just a 2 cent.
Enough theory...time for action?
I think you need to find foods/supplements/activities that help to conserve or improve musculature ...skeletal and tendon strength.
* exercise...probably works...if you do it
* 8-9 essential aminos supplement...seems to work
* glycine / gelatin...seems to work
* strontium citrate...indications
* various mitochondrial boosters
* I use a bathroom door jamb to measure any loss of height...just like growing up...I intend to measure any growing down. If I start to shrink...I'll have a fit and start hanging from an overhead bar a lot?