Fight Aging!

This is another group selection argument. The problem with group selection is that there is no plausible molecular-biological mechanism that could drive it.

I think group selection is driven by an ideological bias, one based on collectivist ideologies such as socialism or communism.

What about internal evolution?
Your mtDNA could evolve (in ways akin to a cancer whereby it doesn't reciprocate) and one mtDNA "species" could fight others for control of the cell and cells, at the expense of the body.

Evolutionary Inertia: Evolution often builds upon existing mechanisms rather than inventing entirely new ones. If programmed death evolved in simpler organisms where group selection played a more significant role, this trait could have been inherited by more complex organisms, including humans. Evolution tends to use what has worked before, leading to the persistence of traits across species.

Evolutionary Conservation of Traits: Evolution tends to conserve traits that are beneficial for a species. If programmed death were detrimental to a species' survival, it would likely have been selected against. The fact that programmed death is observed across various species suggests that it may have evolutionary advantages.

Mutation Accumulation: Over time, organisms accumulate mutations in their DNA. Some of these mutations can be deleterious, leading to decreased fitness and increased vulnerability to diseases. By limiting the lifespan of individuals, evolution can reduce the chances of these harmful mutations becoming fixed within a population. (s. also H.J.Muller's "genetic ratchet")

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Regardless of if. the aging is mildly selected for or if there's an antagonistic pleytropy in play there's very little selection against aging. We have a cellular example of programmed death in the form of telomere shortening and apoptosis. If it can happen on cellular level it, for sure, can be selected for in some species.

The problem is that there's no single switch or clock that leads to a programed death.

Hi there! Just a 2 cents. TL DR: sexual resources/sex vs longevity thing at play (specie survival/adaptation/evolution).

A human is sexually reproductive by 9-13 years old. It lives up to 120 years.
A greenland shark is sexually reproductive at 150 years old. It lives up to 450 years.
A icelandic clam is matured sexually at 35-45 years old. It lives up to 530 years.

Overall, there is a trend....for mammals; that the longer the life...the farther, in their life, do they become sexual reproductive/enter the 'adult mature state/sexually capable/post-puberty'.

Puberty/sexual capability = (life) costly.

Some animals, though, seem to able to live on...even if they may have reproduced relatively quickly, in their life.

So, overall, sexual reproduction is very costly and is taking away somatic tissue/DNA repair resources; i.e. resources are diverted for/to sexual reproduction..instead of repair/Longevity.
A (resources) juggle/juggling between both specie purposes; longevity vs reproduciton.

Humans, live relatively long, but compared to some other animals....no. It's not That, long...
Long...yes, century long....is long; but is stil 1 century, no more. And, no 9 lives 'rayovac cat'.

It seems, that, a balance can be found, where the animal can obtain a much longer life - AND - still, be able, to have a 'long period of sexual reproduction/window'...before menopause and
andropause.

Recently, it was found, that apes (chimpanzees..and, mostly likely too Gorillas/Orangutans/Bonobos/Macaques/Mandrills/Capuscin..) suffer of menopause (for females apes). I mean, it makes sense, humans, are apes...just a different offshoot of cave age/ancient ape-like hominins (we are h. sapiens; long ago, it was h. erectus, and other australopiths);
and, for male apes,...same as human males/men....andropause.
Loss of testosterone; and for women, loss of estrogen; which confer protection to the person;
it was shown that testosterone...is a 2-sided hormone...it's important for males; and it can be 'aromatized' to estrogen...in male body (via Aromatase); like changing aroma/fragrance...
the reason?...is because, estrogen has a more protective effect...many males, it was found, that shoot with testosterone or steroids....could suffer; testoterone...it seems, could increase the power, strenght, muscularity....and yes...anger/confrontation...specifically - Competition.
Testosterone...was all about competition. While, estrogen, the inverse...it was about, Support.
Women that get testosterone boost or loss of estrogen...can become much more adversarial and competitive; even downright grumpy..etc. Estrogen receptors are very present, in both gender bodies; in fact, in human brain and everywhere else; you find estrogenic receptors; that activate Telomerase...so, I mean, that's why testosterone can be benefitial; because it is reconverted to estrogen, to activate estrogenic receptors; and obtain telomeric DNA elongation (via telomerase enzyme--estrogen receptors). It is also why..women live longer; because of estrogenics powerful effect on the cell, it helps the cell and, with telomerase, can quench ROS..telomerase not only elongates (telomeres);....it quenches mtROS when it leaves its nuclear compartment....flys off..in the mitochondria to do its quenching magic. Then, once done...it goes back again..to nucleus...to continue its main job (elongate telomeres and fix short telomere uncapping/fusion/recombination)

The problem, is that, excess testosterone...has deleterious effect in humans (and ape, for sure); it can literally speed up the whole agin process...and it accelerates the sexual capability (some steroids, though, actually reduce sexual capability..when in excess..)....so it seems that males can have a shorter life..because of their hormones, which if not converted to estrogen,...end up used for sexual capability and strenght/power/competition...even to a certain 'virility'/'agression'...
It was demonstrated...
in Gorillas....they can be extremely strong, vicious, viril, angry (chest thumping/smacking), 'fight other apes'....just very protective and 'territorial'...in essence, can turn violent quick.
That means, that testosterone boosted the power/muscularity...of such apes...or in men, like body builders...

But, the downshoot of this, is activation of the whole mTOR/Rapamycin pathway....we know, that excess activation mTOR..accelerates senescence....so, I mean, you might have 400 lbs of muscle...like Gorilla...but, it's not good for 'longevity'...it is (mostly) only good 'sexual reproduction' and 'strenght/muscularity/defense/arm/body-power'.

It is oftenly called the 'alpha male'....alpha maleship..is seen in Gorillas and other apes...beta males (pej.)...oftenly lose fighting and just do not 'get sex'....I'm not kidding, am serious. In fact, it was shown that like naked mole rats and certain insects, certain individuals in that whole group....'binge the sex'...they are the 'Alpha males' of the colonny...and Only They have sex/'get some' and mate with the 'queen'....the rest...are 'worker bees'...amorph and asexual (in human equivalent, that is like Euneuch).

So, it is a big 'competition' for 'sex/mating'...to obtain it. In the animal kingdom.
Animals fight each other to obtain the female of choice..to reproduct with.

All this...is costly, in sexual reproduction resources...that I used...and diverted for that; instead...of 'longevity genes' resources... It was demonstrated that women who have more children suffer high gravidity...mitochondrial DNA damage...as in, high pregnancies/repeated gestations...means damage to her life. Reprdouction, It is not cost-less.

So, for humans (and apes...who it has been found suffer meno/andro-pause...and have a redution of sexual hormones too once out fo the 'sex reproduction window/phase'..), it is from 10 to about 55 (for women); and for men, well, it happens around those 50-60s...but, a man can still produce sperm...all life; but yes, the sperm will have higher mutation/defects/damage as he ages
but, older spermatozoids, can have Longer Telomeres...called the 'father effect'; because it had time to 'mature'; it was demonstrated in certain children, taht an older father gave longer telomeres to the child(ren) -- but, with possible defects/mutations. These mutations are not enough to hamper the elongative of sperm's cells' telomeres (telomerase in gonads/testis).

It was seen in amorph/asexual men or men that suffer ED (erectile dysfunction); they, oftenly, have spermatozoa that can be weak when swimming/traveling or distorted; like...the sperm is not 'strong' per se...and the old saying is : ''won't make strong children''; they can also low spermatozoa count; so...all this, is not propice for sexual reproduction. It's not a slight against them...it's just the way mother nature works....it wants 'strong reproduction'...to assure specie survival. It is why testosterone and estrogen...fill, each, their role, in both genders.
A man..is a man...is a man. A woman...is a woman...is a woman.
The more you get in the sexual role/gender...the better, speaking per se, it is in terms of heterosexual reproduction; specie survival assurance/natality.

But, today, it is different...humans live long(er)...and thus, don't Need 'more children'...thus, evolution, would favor longevity...isntead of sexual reproduction.
Like, mice, that can have Tons of babies...they only live a short life..so they 'make up'...in numbers of births...to offset the 'loss by short life'.

If you live 400 years..like a shark....why would you need to put resources in sexual capability...if, basically, all the individuals in this specie....live centuries...there is no 'lack' of 'living individuals'...all of them live ccenturies....Mortality = 0.
Mice = 100% mortality in 2y....= Need 10000% offspring ouput to make up for loss.
Same thing, in insects...why do Queen bees...produce 1 million eggs/offsprings....why so many...
to make the colony survive...because of loss and the worker bees...live barely 2-3 months...
while the 'chosen' Queen...can live 2 years or more. She is crucial to the survival of this specie.
Without her...the whole colonny dies.

With that said, living 3 centuries...like a shark...is rare...these sharks are Rare...not alll of them reach that.
But, one day, we may reach that...and that's when we will change evolution/adapt - it - to our needs; Our need to die, our need to be 'unhealthy', to get diseases, be old'...because 'why not'...
all this, will be over.

It is when ethical/moral problems....will happen. The ethically inclined will (want) to speak for you.
As in, you will live too long..like a shark...and planet, of course, will explode..when no one dies anymore (overpopulation). The same old ethical arguments...will have to be debunked, again.

In the future, it is possible that you could have 0 children....or decide to have 20, like old days...
because, I think not, because when I look at China...I see all I need to understand; govs...and countries...will want to control you, control your body and what you do with it.....curb you'....like China curbing 'number of births' per couple...
to reduce population birthing (China = 1 Billion people...same for India); To reduce (the chance of) overpopulation in China.......overpopulation, again.

If people decide to have many children...of course, planet 'baby boom' will happen again; so, yeah, overpopulation..once more. This is where, I am very in the middle on that point.

I think people will be very divided; those that accept that longevity..means 'people exist'..longer; and as such, they exist on earth...as 1 individual; and this tally Rises...as people 'live forever' and have 25 children large-families, each..

This is where we wil have to think....do we stay on Earth...leave to mars...do we fiind some unexplored terrain (on Earth)...that we could use...for all the new people coming in the future.

'Earth Packed to Seams'....explodes.

When I look at animals...trillions of them...I know we are not There Yet (Planet explosion); but, yea, 8 bilion people on Earth..does tax...Earth...'global warming/weather events'...but, yea, there is still lots of exaggeration in this (and conspiracy/fear mongering 'about the end of the world and planet wil explode...when we are 150 trillion people living centuries/millenias...on it').

I guess, that will be the time to (re)consider 'space tourism' (Elon Musk)...and start thinking about building those Mars or Moon colonnies...not as scifi bs....but Soon(er)...than late(r); and, possibly, in our lifetime (or our (future) lil children's lifetime..maybe, not ours...if too old, already).
They say: ''never too late''....but, with aging...you can be 'too late' (if too old, and it's (stiill) impossible to Really/Truly/Tangibly-- reverse aging...as of yet; so the 'aging'...continues).

Thanks for reading,
just a 2c.

PS: Why would aging be 'selected' (as advantageous/'good', by evolution/natural selection) in certain species?

Because, mainly, for 'quality control'; analogy: taking out/stopping the bad weeds from forming in the whole group.

It's harsh like that, but, evolution/mother nature cannot allow 'uncontrolled' 'rogue' elements to become....like deleterious mutations, for example.

So, senescence, is a protective mechanism, against cancer formation/tumors (via activation of p16,p21, p53 tumor suppressor genes).

Mutations, when deleterious, compromise the survival of the specie (some ''bad weeds/bad apples'' in the whole group); senescence, is the cell's way, to make sure to avert possible negative DNA gene mutations...that would compromise the survival of the (body's) host/specie.

So, you could say, that aging is selected in them/'for them'.......to minimize 'mutational load'.

DNA somatic mutations...happen daily...in our cells....all this increases the mutational load/burden...and this, can in the end...cause chromosomal instability, which will, make for activation of genes, that cause inflammation; this, in turn, will cause more DNA lesions/strand breaks/frags... thus, compromise the individual's life/health/body/cells..

It is called 'hormetic stress' (the benefitial one, in small occasional dose)....but in cancer is called
'chronic stress/chronic inflammation'..this is 'low-to-mid grade' but chronic stress, damage...etc.;
this will activate tumor suppressor genes (p16/53...); then, it will make the cell 'exit' the cell cycle; enter Senescence; Spontaneous Senescence; will with time passing/cell divisions Rounds (mitosis'es)/passages; it is, Replicative Senescence.

Aging, is thus 'selected'...for certain species, by evolution...because their mutational burden...is very high (over time)...Because, they live long lifespans....like Humans....
It was shown in Elephants; that, they have more copies of p53 tumor suppressor gene...

I.e. The Longer You Live...the more chance for cancer/mutations...if that elephant did not have more Cancer protection genes...it would die earlier of cancer; this means, the animal, needs more protection..if its lifespan is longer -- to be Able...to live it/live longer.

Aging, is also a 'curber'....a 'cull' 'the Culling'....well, you can 'reduce population number'...and keep things 'in balance' -> Mortality vs Natality ....balance; it becomes balanced; this keeps the #s correct and keeps the 'survival' of specie 'working'; it balances itself/is balanced...makes survival. Thus, aging, is a 'balancer'/'culler'/'curber'...it's harsh like that...not only is it a 'weed remover'...but also a 'balancer'...by culling -- By Aging them...when people die of age....
And, uneed
like 2.0 Child per woman...to offset the loss of old people dying...she needs at least 1.0 child...
if she cannot have 1.0...but only 0.5 child per woman...it cannot 'replace the deaths/loss of old humans dying of age//..mortality'...this is why I worry...about China...doing the 'culling/curbing'...of number of children..per couple.

@cuberat
'The problem is that there's no single switch or clock that leads to a programed death.'

... and it's more likely not a switch but a dial.
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I'm always amazed at how prevalent the idea of 'flipping the switch and being instantly young again' is in the AA community. Even if we could 'flip the switch' and reverse aging, it would happen only as fast as aging does, limited by the irreversible damage that has already accumulated. One would start to notice and measure considerable changes after several years, probably seven or more. So, perhaps the 'switch' has already been found, but no one has noticed."
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Vince Giuliano
https://www.anti-agingfirewalls.com/2023/04/04/healthy-active-and-productive-till-100-laying-out-the-adult-aging-process-a-breakthrough-and-my-personal-story/
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Has a rather interesting, convincing even, line of thought:
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'Lifelong changes in histone methylation, particularly double and triple methylation at the H3K37me2-3 locus, inactivates many repair and maintenance genes, such as the ones that empower stem cell activation for tissue renewal. The Polychrome Repressive Complex (PRC) sees to this methylation in adults, as necessary for repression of early growth and development genes starting typically in a human's mid 20s.. As we grow older the methylation gets more and more intense, and our natural renewal processes get weaker. DNA repair is less efficient and reliable. Protein production gradually becomes less reliable. In the absence of adequate renewal and repair, many tissues function less well and become inflamed. They produce proinflammatory cytokines which are circulated body-wide via the cardiovascular system, like TNF-alpha, IL-6 and IL-22. This inflammatory progression may start in a person's late 60s, become more pronounced in their 70s and dominant in their 80s.
The resultant systemic inflammation acts on the hypothalamus and autonomous nervous system so as significantly generate more systemic inflammation, such as by transforming Type 2 (anti-inflammatory) macrophages into Type 1 (inflammatory) macrophages. Acting through the PRC, this further increases the rate of aging (progressive changes in histone and DNA methylation state ). So there is a positive feedback loop leading to accelerated aging and multi-system deterioration near the end of life. Most people are dead before reaching 90, very few are alive to 100, and everybody known to history is dead by 123.'

Jones, An interesting read but my thoughts on why you won't get a huge age appearance reversal with a large epigenetic age reduction is that the bodies repair mechanisms are in that state by about the age of 24 where it won't be able to fully repair all the damage to its previous state. Not even considering some extracellular issues my guess is if you treated someone with Yamanaka factors or Katcher's E5 etc to get a very large epigenetic reversal the person would probably look around 10 years younger in a few months (not years) but the health readings of their organs would show a much bigger effect. I don't expect skin collagen and elastin etc to give more than that 10 year reduction. Also I think the person won't fully regain the capability to have the strength they were capable of at 30 even if the methylation etc says they went from 60 to 30.

@Michael
I was referring to "flipping the switch" of the aging program, not interventions that directly and drastically change the results of the program (i.e. repair). Those should show effects faster.
Sorry, I didn't state that explicitly.

@Michael Best "you won't get a huge age appearance reversal with a large epigenetic age reduction"

The main component of visual age reversal is tropoelastin. I've haven't seen any epigenetic age reversal restarting production of tropoelastin. So only supplementing hydrolized elastin (mimicking to an extent the natural tropoelastin) is available. Supplementing hydrolized elastin works by my subjective visual estimate best by removing deep wrinkles, 2-3 years worth of newest wrinkles very fast in 6-8 weeks months removed, then further improvements in skin rebuild halt to a slow crawl. Old wrinkles are scars plain and simple; these rebuilt very slowly. This is rather new, so there is no estimate how far improvement it will cumulatively make. Your "don't expect skin [...] to give more than that 10 year reduction" is by my subjective pessimistic experience... highly pessimistic.

PPS: Great comments...It's about right...most of the epigenetic aging reprogramming...will, probably on average, yield a 10-15...20 years lifespan rejuvenation; that's being optimistic...not pessimistic; Realistic. The reality..is it is not enough; so that we could repeat it on and on...it's called 'partial' reprogramming...because it only (evidently) partially reprogram the cells - no total/full reprogramming (which is, deadly to environment/cells and was shown in mice..that obtained full reprogramming...they died from doing it). Cells can be reversed, but if they lose their signature/phenotype...they de-differentiate back to stem cells...and that is killer; you can only partially reverse it to keep the 'mature(d) signature', like, as if, keeping the cell's 'memory'... if you erase it like a clean slate...you 'erased' the cell....identity.
That's the differentiation of the cell...de-differentiating/reverting back (from its matured 'signature`'/differentiated state) to a stem cell (De-differentiated state).
The reason why it is deadly...is because these cells have use/purpose...in their current state/age/mature state....if you remove that..it is (akin, again) like 'clean slate' 'erasure'...
Like losing alll your memories in your brain/your identity..and you become amnesiac
with complete memory loss/lost...you don't even remember your name/who you are...or your family, neither (as if these 'events' --never happened)...like, in Alzheimer's...
It's, also, like all your data on your hard drive...is wiped (out, forever) after a pressing 'Delete'.
(well, actually, it's false; even deleting data on a mechanical SATA hard drive...is still there; even if you deleted it. ONLY..if your COPY over it....then it is gone forever. Copying/Overcopying/Overwriting...data....destroys data forever..because teh new data,,,takes place of the old one, is REPLACED by the new one. (So be careful, with your data..to not overwrite the good one...that you need; because, the instant you overwrite it...gone, forever).
I.e. just like 'having new memories' in your brain (injected in it)...that you never lived/experienced...'a new program/memories'..were uploaded in your head (yes, just like Keanu Reeve's Johnny Mnemonic, I AM Robot, A.I. and The Matrix films). You wake up and you think you're a (new) person...your old person/identity --is gone, because the memories recollection/data' in your neurons..has been Overwritten..with new ones. the old you, does no exist anymore. It sounds very scifi (like these movies)...but it is not; it would happen exactly like that.

IT's why partial reprogramming is limited (still)...also, it was found that the damage incurred/accrued so far...could simply not be repaired...despite these repeated rounds of reprogramming; we, clearly, gain 'permanent' or (near) permanent (irreversible) damage.
I mean, we should be able to repair all damage; but, it seems, it's impossible, the damage takes over (always), in a stochastic process and just an excess of it, which compromises the life and overburdens the anti-inflammatory, DNA repair (NHEJ/BER/Helicase) and antioxidative systems;
(still) deleterious somatic DNA mutations were found after, despite reprogramming...so it just does not go...not enough...

So, it sounds about right...like CR(Calorie Restriction) that epigenetic reprogramming will help to give 10 year in humans...of bioage reversing...roughly. Which, I know, is so underwhelming but better than nothing (again). You think to yourself: ''I'll just stick to CR..and doing push-ups..''.
...hey all the while smoking 1 pack of cigs a day...just to 'drive it' -in...(i.e. drive -yourself in - the (under)ground). It seems to reach, also, what Senolytics reach..which is about 10 year of lengthening of average lifespan...maybe 5 years boost of max. lifespan,...tops.
But, most of this, is weakly 'synergic'...so not really a 'multiplying effect'...i.e. it'S not because you do senolytics, you do CR, you take collagen and you did epigennetic reprogramming that, necessarily, you will get 20-30 years lifespan extension; I mean there is 'addition' effect...but it is lesser and lesser...the more your add stuff...''diminishing returns''...it is due, to 'redundancy' gene pathways that many of these interventiosn ...all work at/same way...so there is no more 'extra' effect to get (you are getting the 'optimal' of it...Already, even with less need of doing different things). It'S why, sometimes, a Single Thing...can be more powerful than tons combined....
Albiet, with aging, it is clear that the latter..is needed; almost nothing 'alone' will reverse aging..
thus, a 'multi-prong' approach to solve aging is needed....multi-attacking it from 'all angles'...

Sadly, the 'program' (epigenetic program)...is not enough; even if we tinker with it, in the methylome; it demonstrates that Largest cause of our aging....is that DNA damage accrual and the lack of repair of it; happening every second you breathe in O2..making mtROS from mitochondrial lipoperoxidation and ETC radicals reaction/electron leakage/ATP production loss.

I always believed that reprogramming...would revert it all...back to how we were when 20 years old..........alas.

The only real way to slow aging, tangibly, is by dealing with the damage/repairing;
if we can't repair it, lifespan will be average/same old...

If we can't repair DNA SSBs/DSBs/frags...then we can focus on slowing the methylome changes...via epigenetic reprogramming; but, as you saw...it's not enough;
so, it means, that our RATE of global dna demethylation must be changed/slowed.
It was demonstrated in a Russian study in 1980s...cows (25 years lifespan) demethylated 4 times quicker than humans; horses (30-50 years lifespan) about 2-3 times; mice (2-3 years lifespan) at about 100-times. This was Also apparent in telomeres...mice's telomeric DNA shortening rate..was 100-time quicker than humans (mice 5000 bp (loss)/year Vs human 50 bp (basepair nucleotide telomeric TTAAGGG repeat DNA) loss)/year).

Programmed death speeds up evolution of a species. If a competing species is evolving faster, then the slower evolving species will disappear