An Interesting Theoretical Paper on the Nature of Aging

Today I'll point out an open access theory of aging paper that I found intriguing, given that it represents a fairly different viewpoint on aging, seemingly assembled from portions of other mainstream views on theories of aging. Almost every faction within the aging research community would find parts to agree with, parts to reject, and parts that will make you think things through. If you have strong opinions on theories of aging, you'll probably get a lot out of it. The contents defy short summary, but the more important points seem to be the idea of aging as an absence of process, as a lack of maintenance systems, and a rejection of the idea that the fundamental mechanisms of aging are as universal as the present mainstream consider them to be.

I've made the point in the past that lack of progress towards effective treatments on the part of the dominant paradigm in a field of medicine tends to lead to a lot of alternative, competing theorizing. It is much cheaper and easier to produce hypotheses than to undertake research programs and trials. Aging research has been stuck in this state for quite some time now, and, since the molecular biology associated with the progression of aging is immensely complex and poorly understood, there is a lot of room for theories to flourish without the possibility of effective contradiction. Cellular metabolism is in and of itself immensely complex and incompletely understood, and the effects of aging at the detail level are a large superset of all aspects of cellular metabolism, extending out to include the ways in which this intricate group of systems changes over time. So, and in recent years especially, there has been a great mixing and seeding of ideas when it comes to the fundamental level of theory regarding aging, and little ability to cull the field with clear and direct evidence.

The vast complexity of our biology, and the equally vast cost in time and money required to map it or manipulate it, is what makes the SENS damage repair approach to rejuvenation treatments very attractive. For all that the progression of aging is yet to be mapped in detail at the cellular level, for the reasons given above, the research community does have a good understanding and a good, defensible list of the causes of aging. This knowledge is complete enough to design and build effective treatments to block, repair, or reverse those causes, and those plans and research programs exist. Taking this path is comparatively cheap, in comparison to trying to understand or manipulate the operation of cellular metabolism, and effectiveness can be proven by building and testing. It is an end-run around gaps in knowledge and the expense required to fill them, taking the engineering approach to the problem. In fact, I see this as the most cost-effective path forward to determining the relevance of various theories of aging, and to answering many questions on the role of specific mechanisms in cellular biology in aging.

Given that we have the potential to address aging, to intervene effectively and extend life, I think that more important as a goal than theorizing. There is more to learn and more to gain by taking action in the present state of aging research, by building the comparatively cheap first wave of rejuvenation biotechnologies such as senescent cell clearance treatments, and then evaluating their effects. I think the character of the field of aging research is going to change dramatically in the years ahead as a result of the advent of SENS-style rejuvenation therapies. Theorizing will decline in favor of discovery and evaluation, with directions for research following on from the most effective therapies and their impact on metabolism. For now, however, on with the theorizing, and note that the quotes below are only small sections of a long but very readable paper:

Principles of alternative gerontology

Damage itself does not mean aging. Senescence is observed only if the effects of these negative events have not been eliminated. One can conclude, therefore, that senescence takes place only if allowed by low effectiveness of life programs of a particular organism. In other words, senescence is a result of allowing for manifestation of unavoidable effects of various adverse forces. As shown below, the degree of that allowance is different in various clades. Considering that the same forces can disrupt various organismal functions in varying ways depending on a particular organism, no universal mechanism of aging can exist. For example, oxidative damage to cells of Saccharomyces cerevisiae does not include various destructive processes resulting from peroxidation of polyunsaturated fatty acids, as the latter are not produced by the species. On the other hand, accumulation of rDNA circles noted in yeast is not found in human cells where an open mitosis process is observed.

Aging is not a genuine trait. Aging evolved only as a side effect of the choice of a particular life strategy of a clade. As such, it corresponds perfectly to the term "spandrel" introduced by Gould and Lewontin. With that in mind, gerontologists would be amiss to look for any universal mechanisms of aging because they simply do not exist. As a rational consequence, in order to explain the mechanisms of human aging, it is necessary to use the closest possible relatives of human beings as model organisms of gerontology. Accepting the interpretation that the incidence and nature of aging processes are side effects of the chosen life strategies rather than genuine traits suggests the need to transform the methodological approach to the phenomenon.

The problem of aging of animals practically does not exist in natural populations. Animals in the wild rarely survive until the symptoms of senescence become visible. As a biological science, gerontology is now strongly supported not so much for transcendental reasons, but rather because the age structure of the developed societies will soon create economic and social problems. The most important goal for such studies is to diminish the costs of population aging. Geriatrics needs a scientific basis for improving medical practice. Consequently, the aim of gerontology is to prevent the most life-devastating symptoms of senescence. Therefore, the basic role of gerontology, at least in the short term, should be identifying mechanisms that slow down and minimise the effects of senescence. In other words, the role of gerontology is not to extend the maximum lifespan above the limit characteristic for the given species. However, rather disappointingly, this is precisely what experimental gerontologists have been doing: rather than looking for mutants of various organisms in which the symptoms of senescence appear later or are less detrimental, they have been mainly looking for mutants with increased lifespan.

In human beings the term "aging" means appearance of symptoms of senescence and increased probability of death at advancing age. However, after an analysis of various life forms, one can conclude that senescence and unavoidability of death in general are at least partly separable in mortal organisms, while numerous groups of simpler animals are biologically immortal. The phenomenon of senescence is observed in those species or life stages of organisms that cannot by principle remove the damage done by various adverse extrinsic and intrinsic forces. An analysis of differences in life programs among various taxonomic groups of animals as well as within a particular group allows for a generalisation that there are three main aging phenotypes.

The first encompasses representatives of the simplest animals like sponges, cnidarians, annelids, nemerteans or echinoderms that show biological immortality, that is, lack of intrinsic causes of death. These animals rarely manifest symptoms of senescence. The reason for their immortality is the ability to reproduce agametically (besides sexually), resulting from the enormous ability of cell replacement and regeneration. The second group is represented by the organisms which, while being mortal, show no visible symptoms of senescence. This phenotype is a consequence of the constant increase in body size after reaching sexual maturity. Because proportional growth requires constant availability of most of organismal-level developmental programs, such constant growth is accompanied by high cell replacement and regeneration ability. The best known representatives of that group are crustaceans and molluscs among invertebrates and fish and reptiles among vertebrates. Constant growth corresponds to the adolescence period of mammals or larval stages of insects as these animals do not show organismal-level senescence. Consequently, continuously growing animals are "young forever". The third and very diverse group is represented by insects and roundworms among invertebrates and mammals and birds among vertebrates. These animals show evident symptoms of senescence but differ in longevity. Their adult representatives live for a very short time. The presence of symptoms of senescence in these animals results from their primary life programs. Their sensecence is a consequence of the lack of, or very limited, cell replacement and regeneration mechanisms.

The practical conclusion that can be drawn from these considerations is that lack of universality of aging suggests a fundamental change in approach to gerontological problems. Instead of looking for mutants of simple and evolutionarily distant species with increased lifespans, gerontology should focus on finding factors alleviating the most life-disrupting effects of senescence.

Comments

Hey all!

''As a biological science, gerontology is now strongly supported not so much for transcendental reasons, but rather because the age structure of the developed societies will soon create economic and social problems. The most important goal for such studies is to diminish the costs of population aging. Geriatrics needs a scientific basis for improving medical practice. Consequently, the aim of gerontology is to prevent the most life-devastating symptoms of senescence.
Therefore, the basic role of gerontology, at least in the short term, should be identifying mechanisms that slow down and minimise the effects of senescence. In other words, the role of gerontology is not to extend the maximum lifespan above the limit characteristic for the given species. However, rather disappointingly, this is precisely what experimental gerontologists have been doing: rather than looking for mutants of various organisms in which the symptoms of senescence appear later or are less detrimental, they have been mainly looking for mutants with increased lifespan.''

Great paper, very interesting read. Some largess.

And concerning that statement, Yes and No.

I'm holding in, on it, a bit. It is pushing the ethics of gerontology in the large sense ('economic and social problems').
Which gerontology is not about (bio a least). To reduce the cost of aging and diseases by eliminating them is a product of
what gerontology is; and that is, studying the aging; and now, with the intention of doing something about it - and there will be (un)intended repercussions, that have nothing to do with what
(bio)gerontology is from the start. So study the impacts of aging on population and society and such, is part of gerontology; but not biogerontology at least.

They write about biogerontology and try to make it like 'all encompassing' vague gerontology semantic - with a touch of biology in it, because gerontology has a sub-topic of biogerontology, since gerontology is the large word for everything that touches aging.
Biogerontology is the one who will cure humanity - not vague gerontology; you can talk about society all you want and how the effects of aging on it and $$$$...it's the biology that will save your life not the other way around.

The aim of gerontology to reduce late senescence diseases is a great one, but remember it was never the ultimate purpose of it. The starting point was studying aging of aging human
(Gerontology, greek word, geron : old man in old greek, logos : a science/practice/research/knowledge/study in old greek, geronlogos -> geron-to-logy), then that transformed into mysticism, romanticism and total esoterism (thanks to Platon esoterism renaissance in middle ages) with alchemy/magic thrown in
to make humans believe that death can be stopped and immortality is possible (hence old grimoires talking about magic potions/recipes for that youth elixir of eternal jouvence).

Even in the Bible, Adam and Enoch lived to 900 years (though not calendar years, most likely months, not our 'roman calendar years of 365 days'; and then, some atheist/agnostics would say Religion is bs and the religious would call them no-faith good-for-nothing soul-lesss heathens who believe in nothing (but themselves, science and what they see with their own 2 eyes))
and only, god, had (still has?) immortality or was neither nead neither alive, depending on what you believe in the first place (something aberration like stuck in limbo purgatory) a topic in theology too. Jesus resurrected. We could go on about gerontology and religion and science.

Well, now we are in the future, and biogerontology is no bs and makes all these past ramblings pale/fade into oblivion for it is provable beyond a shadow of a doubt, in this very life and repeatable, thus, it may not be perfect (perfection doesn't exist it seems, but animals already reached immortality, like god, so immortality in itself is not perfection? (or whatever ''perfection'' supposedly means in our flawed and imperfect 'mortal' incongruous concepts, calculus and laws we make up for ourselves on Earth and Believe - we Think we know it all. Error. Life is Flawed and we can't even explain what happens after death for humans...many questions are unanswered and are unexplainable by 'low-level human 'mortal' imperfect flawed science).

Still, we are doing pretty good ! : D And, if we can make ourselves immortal and live long lives, then it's really all that matters in the long run. Deep down, at the end of the day, when all said and done, our life is all that matters; and being here, alive, to say it makes a big difference.

''In other words, the role of gerontology is not to extend the maximum lifespan above the limit characteristic for the given species. However, rather disappointingly, this is precisely what experimental gerontologists have been doing: rather than looking for mutants of various organisms in which the symptoms of senescence appear later or are less detrimental, they have been mainly looking for mutants with increased lifespan.''

To say gerontology must aim to reduce senescence is good to reduce diseases and improve health...very good yes, but they are forgetting that in the short term, it's important to improve the diseases of the elderly and also, young ones. But, in the long run, that is not what biogerontology should solely focus on.
It will have to stop studying senescence or make senescent-cell clearance, that leads to nowhere.
I mean, think about it, already senescence clearance is happening, it is not such a major driver, except for major diseases, it increases pathological aging but for intrinsic aging, its replicative senescence and that's very late in the game.

For example, mTOR inhibition by Rapamycin or Quercetin Senolytics reverses cell senescence to cell youth phenotype. Still, have you ever read a study on mouse where rapamycin, senolytics or CR made a mouse live 10 times its life ? No. Never. It will never ever happen. Because, they only act on the pathological senescence, not much on intrinsical senescence.
Senescence (the pathological kind, induble/stress-inducible) is just one thing among many. The only appreciable is replicative end in normal healthy aging people who do not have these diseases or post-pones them much later; still, it doesn't change the fact that humans die before 122, healthy or not.
As such, it is imperative to make sure we are capable of increasing humans maximum lifespan, if we wish to stop their death from old age.

To say :

''In other words, the role of gerontology is not to extend the maximum lifespan above the limit characteristic for the given species''

Is wrong, BIO-gerontology, has always been about that and it is THE ONLY way that DEATH can be twarthed. Even if we live 100% HEALTHY - THE FACT IS WE DIE AT 122-135 MAX. END - OF - STORY.
It's no good to me to read that such scientists don't believe that other scientist who find lifespan extension is a good thing but rather a waste of time. CURING DISEASE is not a waste of time - NEITHER is extending Maximum lifespan.

At least, they say 'in the short term, at least, we should prioritize on senescence/diseases (of old people to make them healthy and less suffering - and SURPRISE (!) - die at 122 or before - On Clock). Yes, in priority, diseases are important
and there is LOADS of research/and invention on reducing/abating diseases (I don't believe one second to say :'there is not enough'...THERE IS A LOT done...and yes there can be more...what there is LESS...is studying to increase maximum lifespan...they conveniently omit that fact.
How many frikkin studies talk about humans going above 120s...count them on your fingers..and the centenarians studies are just that...centenarians being studied and it ends there. Literally Nothing about going above maximum lifespan in humans. It's ironic really. It's 90% about increasing the health span of humans to live to 120s and die there, that's it.

''The practical conclusion that can be drawn from these considerations is that lack of universality of aging suggests a fundamental change in approach to gerontological problems. Instead of looking for mutants of simple and evolutionarily distant species with increased lifespans, gerontology should focus on finding factors alleviating the most life-disrupting effects of senescence.''

Basically, they mean, we should cure diseases instead of increasing maximum lifespan. I'm with them on ''Instead of looking for mutants of simple and evolutionarily distant species with increased lifespans'' and it stops there,

what it should be is : ''Instead of only researching curing, though very important and we concentrate 99% on that now, we should, later but soon enough, integrate non-simple and non-distant mutant species that are very long-lived/close to humans, such as naked mole rats, apes, among others that deserve more research than continuing to increase lifespan in little insects, mice, jelly things and squirrels...and saying increasing mlsp is bs like our study''
: D

Posted by: CANanonymity at March 29th, 2016 10:50 PM

In 1989 I started by delusional thinking. Very long life is thermodynamically possible, probable, and therefore inevitable.
If the nominal chemical content of the various cells of the 25 year old body are maintained then the whole body will work as the 25 year old body works. Molecular content can be kept nominal by adding energy to the cellular process that will maintain the nominal concentrations of the thousand or so molecules of each of the 20 to 40 or so types of cells in the body. The concept is simple and clean and rests on the second law: you can do what you want in a chemical system if you pay the energy and matter price to do it. The 25 year old body does it so it can be done. But it isn't easy.
De Grey's method looks attractive because it points to why the molecular nominal concentrations fall below nominal, garbage collection fails to keep up. Help it keep up an you get closer to nominal.
But the De Pinho and Sahan telermerase experiments show that you can keep things near to nominal by keeping the cells from stepping on themselves by unwinding the chromosomes and having genes corrupted.
The stem cell research shows that if we can keep them working their daughter cells will be closer to nominal than aged cells concentrations are.
Parabiosis has shown that the young body produces molecules that keep the bodies various cell types with nominal concentrations. The Harvard group under Amy Wagers, and other groups, says gdf11 and other protein concentrations fall off in the body as it ages and papabiosis pushes the concentrations back toward nominal in the old body with the greater concentration from the young. More than other procedures this tends to support the idea that nominal cell molecular concentrations for each of the various cell types is something that bio-engineering can accomplish.
Rejuvenation and longevity are an information problem: the nominal concentrations need to be documented, their maintenance needs to be understood, and natures failure to maintain them needs to be corrected. The young body does it, naturally. Science will assist the body to maintain nominal concentrations once the research concludes what nominal is and how nature keeps it nominal.

Posted by: Roger Duronio at May 8th, 2016 10:05 AM

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