The Concept of Immune Resilience and Its Relevance to Degenerative Aging
The aging of the immune system is widely considered a progressive loss of functional capacity, such as the ability to effectively destroy pathogens and errant cells (known as immunosenescence), coupled to rising levels of unresolved, chronic inflammation (known as inflammaging). In today's open access paper, the authors are more interested in how well the immune system brings itself back to an equilibrium state following the disruptions of an inflammatory response. They call this capacity for restoration "immune resilience". In this framework, aging brings a loss of the ability to restore normality to the immune system following a period of stress, such as that resulting from infection, and it is this loss of resilience to stress that leads to morbidity and mortality.
Is this a useful way to look at immune aging? It is similar to the view of aging as a whole, a loss of the ability to restore homeostasis in the face of disruptive perturbation, that has been presented by Gero in recent years. At some point, the disruption pushes the body beyond its capacity for restoration, and into terminal decline. Does this building of frameworks lead to any usefully different approach to therapy than the present concept of progressively greater immunosenescence and inflammaging, however? At some point one has to match frameworks to the underlying biology, the mechanisms, the targets for therapy.
Why do individuals manifest such wide differences in lifespan, health status across age, and susceptibility to infectious diseases? One possibility is that variations in an immune trait contribute to these differences. Given that infections are among the most impactful environmental factors that shape the human genome, optimal host responses to these microbial drivers of natural selection may have played a role in increasing longevity. Hence, immune mechanisms may have evolved based on conferred resistance to the ancestral burden of inflammatory stress associated with infectious diseases. Resistance mechanisms could include higher immunocompetence and prevention of uncontrolled inflammation. In contemporary times, these infection-resistance mechanisms may confer advantages for a lower comorbidity burden and longevity.
Our hypothesis regarding the identity of this advantageous trait is immunologic resilience (IR). We define optimal IR as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance and longevity (immunocompetence), as well as control inflammation during acute, repeated, or chronic immune (antigenic) stimulation associated with inflammatory stressors (e.g., infections or autoantigens). IR is rooted in the principle that repeated inflammatory (antigenic) exposures are inevitable throughout life, necessitating allostatic processes that mediate adaptation, ideally returning immunocompetence and inflammation to optimal or pre-exposure levels. With this definition, optimal IR is linked to a conjoined high immunocompetence (IC)-low inflammation (IF) state.
Individuals preserving optimal IR metrics manifested advantages for longevity and survival as well as resistance to severe COVID-19, HIV-AIDS, common acute respiratory viral infections, recurrent skin cancer, and sepsis-associated mortality. These advantages were observed after controlling for age, sex, and/or level of antigenic stimulation. Collectively, our findings suggest that the lower immune status observed with age may be driven by two distinct mechanisms, one being dependent on age and the other attributable to IR erosion/degradation, which occurs concurrently with age but is not dependent on age per se. Thus, among persons of similar age, an individual's susceptibility to disease risks/severity and mortality may relate to their antecedent and current capacity for preservation and/or restoration of optimal IR when experiencing inflammatory stress.
Hi there! Just a 2 cents. TL DR: Immunosenescence/immunity (preservation) is directly related to aging; centenarians preserve immunity (formation of antibodies/immune cell function); thymus, bone marrow (no osteoporosis); no cancer (immune macrophaging them); etc...
When the immune system ages...you age (too) and thus, the door opens for infectino/virus/cancer....The supercentenarian woman that lived 115, have low telomeres in her immune cells (leukocytes)...it demonstrated that she was at 'the end of the road' for the 'maximal lifespan' -- of the immune system; because she was experiencing immunosenescence due to replicative senescence entry of her immune cells -- having reached 115 years (The next MLSP, 122). She died not much later (before 120, within 5 years...after reaching 115). Replicative limit is a problem that we have to solve or else no one will ever live beyong 120-130; due to replicative immunosenescence entry -- as maximal limit to human specie lifespan.
''Does this building of frameworks lead to any usefully different approach to therapy than the present concept of progressively greater immunosenescence and inflammaging, however? At some point one has to match frameworks to the underlying biology, the mechanisms, the targets for therapy''
Alas, mostly, no. And you are right, that therapies/frame works should match to goal...but, alas.
Maybe, At last, we will finally have that. (will take 50 years..)
On Aging Impact, if you read the studies, 8 out of 10 studies are now from China, from Chinese biogerontological researchers living in China. I mean, it can look skewed, but they put their research findings -- there; and so, it looks, as if they are the bulk of all the studies.
Of course, on another research website, there, output is not the same (less); but it's interesting that it shows that China is becoming a huge 'biogerontological researcher'; and, maybe, one day, whether we like it or not; it may end up that China defeats aging. It would not surprise me, in the least bit; with all the 'talk' about China (in past 3 years) having lab-made the COVID-19 virus (or that some animal carried it, and from the lab animal, it spread/in chain to humans; then to whole earth via airflight human carriers/objects-food stained of it/air ambient propagation/spreading).
It's really a population number thing....China, USA (your country), Russia, Brazil, India, Japan...these are Very populous countries..and hence, why, they may defeat aging - as, by their sheer population numbers/much high number of researchers --- will end up defeating aging.
Also, much more dollars $$$$ spent/funded in research; by large countries - because have the funds - by virtue of bigger population/GDP.
That does not mean that small(er) countries can't contribute....but when you see 8 researches out of 10 on Aging Impact USA website....being from China....you know something is going on. Population number and China 'getting in on' (bandwagon) to defeating aging -- too.
And, it'S better so, than not; because, even if a 'less than pleasing' country defeats aging...
it is a 'lesser of 2 evils'. Death or aging defeated by someone 'not wished'. Because, it is so 'globalistic' 'to defeat aging' since every human...dies (of it); it means that we have to 'put our differences' aside....and all chime-in..to defeat this 'monster (aging)'. No other way...
it's a bit like being stuck with your enemy...and if the bomb explodes...you both die...
so you have no choice to 'help' your ennemy (temporarily) to disarm...the bomb. Together.
Set your differences aside, set your 'problems' (with each other) aside. For a minute.
Or, else, you bought explode/die.
Catch 22. When ''The ennemy of my ennemy is my friend; but so is, my ennemy too. ..for..now.''
We will have to 'solve our disputes' later (ajourn/postpone) our quarrels -- to some other day...
Because today, a bomb is happening, and there will be no Other/Following/Subsequent day,
if we don't Join Forces/Co-Operate (for 2 seconds..at least, 'for today') and disarm that bomb
together, today/immediately.
Sometimes, in life, you have to walk away and, sometimes, solving problems - Later...Can be a 'sort' of solution (since it's bad, as 'problems grow' if left unchecked/unsolved/resentment), and in the mean time...you Have To Make Do. With the More Dire situation/Imperativity/Urgency/Emergency (life/death)/Existential situation at hand.
Sometimes, the ''When you can't beat'em...join'em...''...is better, in the now.
Procrastination, is not Always, a bad thing.
AI may end up defeating aging --- that would be the big? suprise....but would people be, So, surprised; I don't think so; it would not be so surprising; that, indeed, AI is/was Needed to defeat aging beacuse it could solve problems and come up with ideas we - never could have - to circumvent our limits/failures (so far) to 'try to defeat aging'.
We couldn't do it.....without it.'
AI is limited (itself/in itself/still rudimentary in some aspects and does not 'think' like a human brain -- but that will change once we make a 'neural/AI human-like brain' in lab)...but that limit is pushed continuously farther as 'it learns', as we train it, as it trains itself; and becomes better, faster...solving impossible riddles -- like aging.
'Sky's the Limit'; for us.
'Sky's the Unlimit'; for AI.
Or will be; the AI will be rocketed (like NASA spaceship) to the Stratosphere -- and Beyond (into the Space/Cosmos Infinite).
But, is Aging reallyyy a riddle...still?
No. This riddle is (ultracomplex) but (very)'mapped' Quite* understood, &thus, 'answered/solved'.
Or, Quasi-Totally, solved. 99% there. It's just that last 1% that is exponentially harder to get - to reach the (coveted) BIG 100/#1st place on podium -- that's the ticket to eternal life.
In life, there are no 2nd places; or 3rd....only 1st 'stands'. Because you only get one shot, one chance, one dice-roll and you only got one life (up to now/we're not yet like Mario Bros, or Rayovac Cat, with - 9 Lifes, if you lose your 9 lives, you press the Reset button). Alas, not in reality.
I am saddened that this are so few studies (because they failed/tried...failed, sadly again) that direct their efforts to the Main (bullet) points of Aging, namely:
- Aging is caused DNA damage accumulating; tons and tons of studies showed it; long lived birds have LESS DNA damage in them...long-live rodents (NMRs) have better DNA FOCI/DAMAGE EXCISION Repair/helicases/repair systems....the damage is Less Consequential in them...because Repaired. It's ultra important, because this DNA damage manifests as acceleration of the whole aging process. Yet...nothing...still. It demonstrates the Complexity and Impossibility (Unfeasability?) of repairing DNA.
- Aging is caused by the epigenetic unstability and acceleration of the epigenetic clock; and the demethylation of epimethylome. By the reduction of the TELOMERES -- telomeric DNA; especially, SUB-telomeric dna; that becomes completely 'open' and 'Accessible'...this means that short telomeres mean 'access to inflammatory genes/code' that is Supposed to Only happen when you're old/lived your whole life, not young.
- Telomeres attrition rate Dictates lifespan -- in ALL animals -- and that'S because as the telomere shrink...they become small and now we ahve the 'Telomeric Position Effect' and DDR (Dna Damage Response) -- this means that shorte telomerse are VERY EXPRESSIVE on the inflammatory genes (i.e the p53, p16 bunch of replicative tumor repressors that are negative replication genes -- meant to safeguard against cancer -- but are Accelerating the process of aging by formation of ROS and the reduction of the DNA content of the telomeres; and the demethylation of them too -- this means advancement of the epigenetic clock 'program/scroll').
- Aging is accompanied by Expression/Activity of GENES -- LOSS -- of Gene Silencing. (due to loss of methyl groups to block so over the genes themselves).
- Thus, short telomeres --> DDR/Telomere position effect/gene access/Activation/expression of Replicative Senescent/Inflammatory Genes...that all contribute to Accelerate the 'killing' of the host; and make 'entry to replicative senenscence'.
- It was demonstrated in Long Lived Centenarians offsprings (versus regular offspring from shorter lived parents)...that PROTECT their telomeres LONGER...than short lived people.
They remain TALLER and Methylated; and SILENCED on the genes. No activation of inflammation. No DNA damage. No 'shortening' of the telomeres/Telomeric DNA. No Advancement/Acceleration of the epiclock. No progerin. No 'fast aging' like HGPS.
- It was also demonstrated in Werner Syndrome and HGPS; they both are Accelerated aging Progeria by accelerated chromosomal dysfunction/disassembly and largescale DNA insults/damage, with acceleration of telomer shortening rate...and demethylation also; as they accumulate 'progerin'. These people live 15-50 yaers....instead of a 80-100+, like regular people or centenarians.
- It cannot be any clearer (in pictuer/portrait); I have been studying (biogerontological/ biological/bio) Aging since 2007...and more; almost 15+ years....and that is the final of it.
99% of the Other solutions are 'work arounds' that fail to deliver the Ultimate LEV and 'escaping' the dreaded death at 100...or the max, 120.
- If you Do Not Solve the DNA problem, and the rest, it is 99% sure we will nver reach LEV; not even with 'body organs replacement' 'rebuilding whole body 100%' or 'stem cell injection'....
it just IS NEVER ENOUGH...to counter the inevitability of aging and (DNA) DAMAGE ACCRUAL.
It is a stocastich process...that is mosty, Permanent* once reached to it. Irreversible.
- This is why, I said, it IS IRREVERSIBLE and Permanent...that we age and die of aging and damage....then I guess, 99% of studies in the future are Futile...and are onlt for 'healthy aging' (misnomer/oxymoron/pretender) purpose- -> Therapeutic and you will die on 'the clock' at 120-130 (or less). We won't even reach 140-150....won't be possible;impossible...
- The Stats showed it...there is a PLATEAU-IFICATION happening...people live longer -- and ALL die at 120-130 FULL STOP. No matter if living longer 'Average Lifespan'. It's a Quite Hard Maximal Human Lifespan limit.
Not so 'soft (limit)'.. after all.
- And, thus, as I said, before, it'S WHY that SLOWING aging be end up the ONLY solution to our problem of 'not being capable of Reversing Aging'....or let's say NOT ENOUGH...if we reverse aging by a - GRANDD '10 years'....it's useless...futile, only therapeutic stuff for healthy living/healthy aging and 'healthy dying'.
- Heck, even reversing by a 20-30 years..is still low...albeit, better...but, in the grand scheme of things;;; a Speck (.)
- We thought living to a 1000 like AdG said....I guess we thought wrong.
- And, it,s why I say, if we CAN'T do it (ever), then we have to 'change plan/PLAN B'...only fools repeat the same thing...and expecting a different result the next time. Enough Fool(ish-ness);
now is time to go to plan b; and plan B; is NOT 'healthy aging'....healthy aging is plan Z/Zee..or worse.
- PLAN B is SLOWING aging...which is the CR/Calorie Restriction BS...we hate...but IT DOES work. Calorie Restriction has Been Proven to Slow Aging -- DNA damage accrual and epiclock advacement, diseases, slow telomere attrition reate AND AND AND restore healthy and SLOW AGING; it is, basically, the Sole True Anti-Aging/'Rejuvenation' intervention, right now.
The rest, nope, it'S very 'mild/to no result'...
- So, our plant b, should be redistributing/reallocating resources toward slowing aging; which I know HAS BEEN TRIED..and failed....hence we only 'found' CR...but that's the error - to stop there. And just accept 'we die, we age...do CR..and that'S all there is to it/nothing else we can do'.
Just a 2 cents. Thanks for reading.
PS: But, there is, something we can do..is not abandon the slowing of aging, if the reversing or the repairing is bad/nill/lackluster...futile. otherwise, we Really Abandon...and we set up ourselves (For Death) and for Assured 'aging/healthy aging'/120 years lifespan max,
'and that's it that's all.
CANanonymity - How in theory could we solve the stem cell depletion problem at very high ages? In rodent studies its pretty amazing how youthful some treatments have "80 year old" mice looking and acting but they seem to just fall off quickly at the end. I am assuming if they didn't finally get cancer most are dying from their hearts giving out etc. due to reaching a point where there aren't enough good cells left.
Hi Mike! Thank you for that and the question. Just a 2 cents.
It is a good question/riddle,
the fact that stem cell injection/therapies having been nice but...that - in the end - the mice still die altogether; and that, overall, stem cell injection..was roughly equal (in terms of effect/potency) to CR/calorie restriction...or that the mice...live 'about a regular life' now...which is great; instead of dying yougner...but 'what about people who Already Live lonng?'....in their case, it is
'Diminishing Returns'/'Redundant Pathways'/Redundancy of effect' -- they already live long lifespans...the effect will be (should be? problably?) lesser....I mean, you need all these pathways multiple protections -- to Even reach old age...and that stem cell injection/CR...improves that - to get it...but what if You Already Have It -- like Centearians..it becomes redundance/futile/less or no effect.
Albeit, for people that are sick/ill/and just have 'accelerated agin' - They - will gain, problably, A Lot. but for other people (just like in the mice studies), it will be much less so (if nill).
This means, I believe, that we are 'quite' 'hard set' for 120-130...no matter how many 'intervetions' you try to slow things and reverse the aging -- IF you don't aim teh things I spoke at length in the previous message I wrote.
IT's very telling...that the mice -- get better, have better health, look younger, and just are 'improved' ---due to stem cells; stem cell attrition/stem cell niche reduction big problem...no more tissue renewal; and stem cells' Telomeres -shrinken too.
This is a Very Telling Tale...Even, stem cells...are 'bound' by DNA problem....so what happens when all your stem cells are delepled/used...and they are 'old'...too. You ahve 'old Adult stem cells'....that will never be 'enough' to counter 'the aging' and tissue renewal need/the tissues will age/get older...and so, you (continue to) Age (even so/despite so).
It is a very (playing) Catch-Up- game. We can't 'catch up' it seems, never enough. This I learned fter studying fifty thousands studies...it's alwaus some catch up game. with aging.
And, so far, we can't (catch up (enough), I mean). To be able to say 'we make Robust reversing/rejuvenation -- that we Can Repeat...on and on (like playing a film/musick vinyl disk on 'repeat' button...and -then, obtain the illusive/theoretical/outlandish scifi, LEV).
''We're always 1 step behind.''.
We need to change that...behind 1 step behind...is 1 step behind, and 1 feet in the tomb.
We have to become 1 step ahead' (of this aging, 'Rubic cube', it seems we can't solve the cube).
I don't know, what 'more' proof, medical/biogerontogical scientists Need -- about mice dying -- wether injecting them with stem cells or not...they stil. die.
But, as you said, they Remain Healthier - Longer--thus, they 'reach their maximum' potential (MLSP) much more often...because tehy are healthier - longer, younger per se...
But there is Dramatic Acceleration - Towards the End of Their Life...and then die.
That's the Plateauing/Plateau-ification..that happens with Centenarians..same thing.
They will die within 10-15...years....at about 120...no matter how many stel cell you throw at them
This mean, I believe, Mike, that DNA damage is the Most Conquential and You cannot just 'twarth it' or 'damp it' 'slightly'....with 'Work arounds' (like smtel cellls); you need something else - and that's (Gettting At) The Cause, of aging; the (main) Source.
Scientist say that lack of stem cell is the reason we age...that we need continous stem cell in our stem cell niche to replace our tissues - which is - true.
But, is just, a small % of the Equation.
And, certainly, not (at the Deeper Level) the 'cellular explanation'...I hope that scientist Can make our stem cell niche produce Forever New Young Stem Cells that Rebuild Our Tissues - Forever.
I hope that, but seeing mice dying and centenarians dying..and they Had stem cells..more than eough....and Still die..
Then, I guess, it'S not the Total Answer..to the riddle; the Rest of the Riddle is that dna/damage thing that is Very consequential to our aging --- what if we solve it... ? IF we do, we ahve Much more chances of beating that MLSP. and staying healthy; animals that live 5 CEnturies....have such...why is it so hard to understand (rather, it'S understood, it's just we fail/we tried..DNA is so complex). Now, we must apply it/make it hapepn.
Thanks again for asking,
Just a 2 cents.