A Call to Focus on Extension of Healthspan, Not Lifespan
S. Jay Olshansky is one of the researchers behind the Longevity Dividend initiative, a long-standing and fairly conservative academic initiative aimed at producing far greater funding for research to slow aging. It is one of a number of groups attempting to change the present academic and public research edifice from the inside. Olshansky recently issued a call to action, arguing for the research community to focus on increased healthspan rather than increased lifespan. From my perspective he makes this argument for all the wrong reasons, based on an expectation that it will prove impossible to produce large gains, say two decades or more, in either life span or health span in our lifetimes. This is actually a fairly common viewpoint among researchers, many of whom believe (a) that the only viable way forward is through incremental alteration of the processes of metabolism in later life, an enormously slow and expensive proposition with a limited potential to produce benefits, or (b) that biology is too complex for the existence of any simple strategy to produce sizable improvements in life span.
For my part, I'm not sure that it much matters whether the focus is on healthy lifespan or overall lifespan, as a comparatively simple strategy that should produce large gains in life span does in fact exist, and is described in detail in the SENS rejuvenation research proposals. The strategy is to identify and repair the known forms of cell and tissue damage that cause aging, that arise as a side-effect of the normal operation of metabolism and have no deeper cause themselves. The best analogy is rust in a complex metal structure; rust is very simple, but the progression of decay as the structure falls apart will be as complicated as its shape. Aging has simple causes, it is exactly an accumulation of damage, but it appears complex in its progression because cellular biology and its reactions to damage are complex.
Since aging and age-related ill health have the same cause, are in fact the same phenomenon, it is the case that repair is the best approach whether targeting either healthspan or lifespan. Competition between researchers and developers will lead to the rapid spread of repair-based therapies once any such treatments start to be tested in earnest. The current enthusiasm and increased funding for clearance of senescent cells serves to illustrate this point. Clearance of senescent cells as a method of rejuvenation was a part of the SENS program from day one, but was ignored by near all of the research community until the first demonstrations were carried out. Now in a few short years, numerous approaches are showing far more robust and sizable effects on inflammatory age-related diseases than have yet been achieved via other methods.
Extension of healthy life span is inextricably linked with extension of overall life span when following a repair strategy. Health persists until unrepaired damage reaches critical levels. To the extent that damage can be repaired, health will last longer. To the extent that health lasts longer, life will last longer. So I think the present challenge is less a matter of where the focus on aging falls, but more a matter of obtaining that focus in the first place. It remains the case that work on therapies to treat aging as a medical condition is a minority concern, with minimal funding in comparison to research programs that only investigate aging. In turn, aging research as a whole has minimal funding in comparison to other fields of medical research. Given that aging is the majority cause of death in our species, and the cause of death of 90% of all people in the wealthier regions of the world that fund most life science research, this is a strange and unfortunate state of affairs. It isn't helped by researchers who declare that only minor gains are there to be had in our lifetimes, not exactly a way to fire up enthusiasm for the cause of human rejuvenation.
Shifting focus from life extension to 'healthspan' extension
Olshansky discusses how human longevity has reached into its upper limits and has little room for further gains. He notes that at the turn of the 20th century, life expectancy at birth in most developed nations ranged from 45 to 50 years. With the emergence of major public health initiatives in the late 19th century - including sanitation and the public provision of clean water - mortality rates dropped, and life expectancy increased rapidly. The rise in longevity has slowed considerably in recent decades, and maximum lifespan has never changed much throughout human history.
"There's been a lot of focus in the news lately about what is the maximum human lifespan, with some researchers claiming that it has the potential to be infinite, but there is a biologically based limit imposed largely by the way in which our bodies are designed, and it can be expressed mathematically." Based on the science and medicine available today, he contends that the probability of any significant increase in maximum lifespan in this century is remote.
"There is reason to be optimistic that future breakthroughs in aging biology, if pursued, could allow humanity to live healthier longer. You don't want to live to be over 100 years old if the last 20 years of your life are spent in pain and sickness. Ideally, you want to compress the years of decay and disease - what I call the 'red zone' - into as few as possible at the very end of life. We should not continue to pursue life extension without considering the health consequences of living longer lives. This will be the only way science can push through the biological barriers to life extension that exist today. Life extension should no longer be the primary goal of medicine when applied to people over age 65 - the principal outcome and most important metric of success should be extension of the healthspan."
Over the past century, the relatively easy gains in life expectancy have been achieved by reducing mortality of younger people; more recently, scientists have focused on how much higher life expectancy can increase and what the maximum lifespan is for humans. The former is a population-based metric that involves national vital statistics for groups of people; the latter is the world record for longevity held by 1 person. Regarding maximum lifespan, only a small proportion of all humans are capable of living to 115 years of age. As such, the probability of any substantial increase in maximum lifespan in this century is remote.
Regarding life expectancy, one view developed in 1990 suggested that the increase in life expectancy would soon decelerate because the easy gains had already been achieved. Any substantive future increases require improvements in mortality at older ages, although components of the human body (e.g., brain, heart, knees) are not designed for long-term use. Others suggested that historical trends in the increase in life expectancy will continue indefinitely into the future due to yet-to-be-developed medical advances and improved lifestyles. Not one of the anticipated high-life-expectancy scenarios is remotely plausible today. In fact, a new trend in the opposite direction has emerged in much of the developed world, indicating that death rates for many major causes of death have either leveled off, experienced declining improvement, or increased since 2008.
Reductions in childhood diseases can occur only once for a population; once such gains are achieved, the only outlets for further gains in life expectancy must come from extending the lives of older people. Given that multiple fatal conditions accrue in older people because of biological aging. Once survival past age 65 years becomes common in a country, life expectancy gains will decelerate, even with medical advances and improved lifestyles. Because the point of diminishing returns on life expectancy and the longevity limit for the species has been approached in many parts of the world, there is good reason to conclude that the goal of life extension has largely been achieved.
The conventional approaches used to counteract the diseases of older age have been to improve behavioral risk factors, find ways to detect them earlier, and use medical technology to extend survival for those who already have diseases. The more important goal of public health, medicine, biotechnology, and the health sciences should now shift toward delaying and compressing the period of the lifespan when frailty and disability increase substantially. Referred to as the first health revolution, this new approach for public health (which is to target aging) is seen as a highly effective method of primary prevention.
A consortium of scientists as well as public health experts and organizations has formed with the purpose of developing this new approach to extend healthspan, address the diseases of aging, and help to ameliorate the economic challenges of an anticipated rising prevalence of late-onset diseases. This effort is called the Longevity Dividend Initiative or geroscience. Clinical trials designed to target aging have been approved by the US Food and Drug Administration, with the first trial set to begin in 2019. Large investments in aging biology have already begun through Google's Calico and Human Longevity Inc. The National Institute on Aging has established the Interventions Testing Program to rigorously and quickly test prospective aging interventions for free. The National Institutes of Health has reduced the barriers between its disease-oriented research silos, and the American Federation for Aging Research is spearheading a global effort to secure funds to launch the Longevity Dividend Initiative in 2019. The time has come to recognize the achievement of life extension. Efforts should be focused on achieving the goals of extending and improving the healthspan.
There is no real difference between modest aspirations and a determination to fail. Aim low, and the results will definitely be a disappointment. To pick one example, there is good evidence to suggest that the present outer limit on human life span is determined by accumulation of transthyretin amyloid in the cardiovascular system, leading to heart failure. This is what kills the majority of supercentenarians, based on autopsy data established after David Gobel of the Methuselah Foundation thought to ask Steven Coles of the Gerontology Research Group to check on cause of death. A number of companies are presently working on ways to clear transthyretin amyloid from the body, and there has been one quite successful clinical trial of such a methodology. What then happens to this vaunted limit on human lifespan once it is possible to remove this form of metabolic waste, a form of damage, that degrades cardiovascular function and kills the oldest people? All of aging is this way, all just damage that is amenable to repair.
It's the same old fear of change. You should die on schedule, only a little healthier.
F*** healthspan! I don't want to die, like all other people in the bottom of their hearts, even if they don't say so! And yeah, that means immortality!
Of course I know that healthspan and lifespan are basically the same. You can't change one without changing the other, but heck, I'm tired of having to apologize for desiring not to die. Tired of the stupid taboo and the mass delusion, as if the rest of the people didn't care about death.
"Olshansky discusses how human longevity has reached into its upper limits and has little room for further gains."
When I heard this before...? Oh yeah!
https://ourworldindata.org/wp-content/uploads/2013/05/ourworldindata_record-female-life-expectancy.jpg
Preach it Antonio. We have the light of consciousness and I don't want it to ever be extinguished.
Well, if you can deliver health span, that would give us all a few more decades to get to the point of increased life span and LEV.
Of course, he thinks of incremental improvements within HS. There is basically no news here
I view 'increasing healthspan', as the politically correct terminology average people like the sound of and agree with. Whereas 'increasing lifespan', is the real revolutionary aspect, that average people probably will get scared of, and its too hard to convince them of points.
Where we should introduce people to 'increasing lifespan' is after a number of life extension products are on the market and delivering results for a few years.
At the point the CEO's of the life extension corporations can say, 'our goal is to increase the quality of life for people suffering from illness, but hey if in the process people live a couple of extra years we'll take it.'
You see 'a couple of extra years'(for people suffering from illness) is a step people can handle.
The point I think you are making is that the decision makers can start believing their own bs, and aiming for a 'a couple of extra years', instead of thinking big.
Hi! Just a 2 (big) cents. (TL DR, this one is long, I apologize, it's about epigenetics, have a go at it).
I'm not sure anymore about health equals age/aging/longevity, and vice versa. Both are needed, but there are nuances in the word health, and
using it like that is understandable and 'all encompassing' umbrella term; but health is very hard to pin down as 'something'.
And, if we do pin it down, we realize it is not aging/age, like we think it is. I do believe that health is necessary for longevity
but it is not the 'driver' of why we reach the age we do and not deterministic of human maximum lifespan. You need it, but it doesn't Control
the aging process, it is (co)inter-(in)dependent, it's freaky like that but was carefully made so as a balanced feedback between genes that control health and does that control aging,
thus it's both at the same time but when you look at deep down you see that
you Can differentiate them, yet they are 'one and the same thing', or at least, a part of each other/entwined/completing selves/in balance, but
to say health = longevity, only would mean whatever the maximum of human lifespan we have (122-130 if going by Jeanne Calment elle-même). This limit is hard coded, pure and simple,
for humans at least.
The more I learn about epigenetic aging, the more it freaks me out and tells a whole other story that is simply not present in the aging decor we know
of now, or let's say, we don'T think much of it but I am starting to 'get a big picture', not a pretty one. I recently reread the Horvath and others
result on epigenetic DNA aging and it made me realize, we think we know, but actually we don't and we are erring more than not.
1.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786029/pdf/41467_2017_Article_2697.pdf
Here a few pointers:
intrinsic epigenetic age acceleration (IEAA), extrinsic epigenetic age acceleration (EEAA)
''IEAA
measures cell-intrinsic methylation changes, exhibits greater
consistency across different tissues, appears unrelated to lifestyle
factors and probably indicates a fundamental cell aging process
that is largely conserved across cell types2,6. By contrast, EEAA
captures age-related changes in leukocyte composition and
correlates with lifestyle and health-span related characteristics,
yielding a stronger predictor of all-cause mortality''.
IEAA is what you would call the 'intrinsic' 'aging' process, by DNA methyl clock; internally-made (not by external forces on you and your actions that affect your body/epigenonmic biology).
While, EEAA, is what happens by your lifestyle and environmental exposure; thus not intrinsic, you expose yourself to a bad lifestyle (smoke, eat crap procesed food, stressed, become diseased (because of bad diet, drinking/smoking..) etc...), and live in a shthole (poverty, stressed, etc),
it's why your EEAA will suffer and be 'older'/accelerated - This, we can call 'health'. It is 'extrinsic' and externally-made.
''Epigenetic age
acceleration in blood is associated with cognitive impairment,
neuro-pathology in the elderly8,9, Down syndrome10, Werner
syndrome11, Parkinson's disease12, obesity13, HIV infection14,
and frailty15, menopause''
''DNAm age shows no apparent
correlation with leukocyte telomere length (LTL), whose pace of
shortening in cultured somatic cells has been referred to as the
'mitotic clock'. In vivo, DNAm age and telomere length appear to
be independent predictors of mortality''
This means that the telomere shortening (as seen in progeria HGPS with 500 bp/year loss vs 50 bp/y regular human) and epigenetic age
correlate to mortality - but telomere shortening does not correlate to 'intrinstic age/aging' that is the domain of the epigenetic clock.
It's why there was discrepancy in telomere studies, it's not because telomere shorten suddenly that the cell's epigenetic age rises.
Demonstrating 2 of the same thing, yet different at the same time.
Here is demonstration of that:
''Single-time point analyses
(Fig. 3d) showed that TERT-expressing cells exhibited a linear
relationship between time in culture and the Horvath estimate of
DNAm age (equivalent to a DNAm age of 50 years at 150 days),
whereas in non-TERT cells DNAm age plateaued (equivalent to a
DNAm age of 13 years) in spite of continued proliferation to the
point of replicative senescence. Notably, DNAm age did not
increase in TERT-expressing cells that received regular media
change but were not passaged throughout the entire observation
period of 170 days (right most bar in Fig. 3d). These cells were
not senescent, given that their subsequent passaging resulted in
normal proliferation. In multivariable regression analysis, the
associations of DNAm age with cell passage number and cell
population doubling number were highly modified by TERTexpression
(P-interaction: P = 1.6 × 10-6 and P = 4.0 × 10-5,
respectively; Supplementary Table 9). In the absence of TERTexpression,
DNAm age did not increase with cell passage number,
cell population doubling number, or time in culture.
''
It's pretty amazing (and sad for us) that (our) human skin fetal fibroblasts expressing telomerase transcript (hTERT), when passaged in cell culture, reach a DNA methylation epigenetic age
of 50 years at 150 days passaged/continued proliferation.
While, cells with no TERT ended around 13 years of DNA methylation age, to replicative senescence.
And, cells with TERT, but not passaged, did not experience any DNA methylation age increase.
''Interestingly, one loci associated with IEAA mapped to the TERT gene.
This finding associates accelerated epigenetic aging with telomere elongation/longer telomeres, an unexpected outcome In vitro analysis confirmed that TERT expression in human primary fibroblast cells leads to increased epigenetic aging, which studies have linked to multiple detrimental signs of aging.''
This means that TERT/telomerase itself alters the intrinstic process of aging - towards Acceleration of intrinstic age (by DNA methylation clock).
Why would it accelerated aging if it increases telomere size:
'feedback compensation', antagonistic pleiotropy, telomerase is responsable for the danger of cancer appropriating it, but
that's not the entire reason. Telomerase is a double edged sword, because it increases telomere length - which rejuvenates but does Not rejuvenate intrinsic DNA methylation age.
What it does, it increases DNA methylation aging/age towards accelerated aging. It does so, because a body with high telomeres is in 'accelerated growth',
which means possible cancerous formation/mutagenesis and acceleration of the 'developmental growth' of the body. Don't ask yourself
why the longest lived animals are the Slowest to reach puberty/sexual reproduction, that's because cell dynamic is tied directly to body growth and speed of metabolism. Albeit, body mass/size can be uncoupled from metabolistic speed; but, not for 'developmental growth' the one that is under IGF/mTOR/hormonal endocrine 'growth' factors (testosterone/estrogen/etc. It's not a surprise that the body has estrogenic receptors that when activated, activate telomerase itself; while, testosterone is converted to estrogen via aromatase, to activate estrogenic receptors and Obtain telomerase activity...
then this means, accelerated DNA methylation aging Upon estrogenic activation, because it equals to estrogenic 'sexual reproduction' hormonal capability with the added effect of telomerase activated)...in the study, they said 'age at menarch/menaupause was associated with Increased IEEA', demonstrating that telomerase is a 'pro' aging factor but also, as a compensating reward, it mitigates damages -WHILE increasing the epigenetic DNA methyl clock - 2 FACED.
It DOES NOT redude IEAA, it increases it and that is the biggest problem. But, it all makes sense, it a Negative Antagonistic Pleiotropic Mechanism, that is only meant to 'promote 'healthy' aging', telomerase keeps things healthy enough/by increasing telomere size - But as a Negative, it accelerated the DNA methyl clock.
What does this mean? IEAA and EEAA are 2 different thing, and both reach 'aging/longevity' and 'health'. But only one of the two dictates maximal lifespan.
EEAA is responsible for changes in your health - IS SEPARATE from IEAA, TERT ONLY associated with IEAA on chromosome. Proving that telomeres themselves are simply 'mechanistic replication brakes' to enter cell senescence; but that if the cell is passaged (which equals to what happens over a lifetime), then
it is 'intrinsic' aging we are talking about in that case - and that is the IE DNAm (Intrinsic Epigenetic DNA methylation) clock.
IE DNAm is your 'epigenetic signature/phenotype'. IT'S truly impressive that they said :
''...offspring of
centenarians exhibit a younger DNAm age.
Decreased epigenetic age of PBMCs from Italian semisupercentenarians
and their offspring''
If I remember, centenarian offspring/and centenarian themselves were 8 years younger by epiclock than rest of short-living population.
This is 100% proof that health and aging, are 2 different things, yet the same, but can be distinguished by their effects over time.
IF, centenarians, and supercentenarians can live to a 100+, then it means intrinsic epigenetic age (IE) was the precedent/of precedence in terms of Longevity - Not health, (which is tied to EE). Extrinsic aging seems like a secondary thing/layer on 'top' of the intrisic one. Intrinsic one is unconditional/controls longevity, extrinsic one is conditional/controls health.
''Trade-off: implied in between telomere
length and DNAm age''
What's more is that
'' For IEAA, nuclear transport (FDR =
0.017), Fc epsilon RI signaling (FDR = 0.027), and colorectal
cancer processes (FDR = 0.042) were implicated. For EEAA,
mRNA elongation (FDR = 0.011), mRNA transcription (FDR =
0.018), and neurotrophin signaling pathway (FDR = 0.042) were
implicated (Supplementary Table 10). The GO gene set involved
in telomere maintenance showed nominally significant enrichment
with IEAA (P = 0.04, Supplementary Table 11), which is
consistent with our results surrounding the overlap between
IEAA and telomere length associated genes.''
Again, as soon as you touch telomeres to lengthen them or maintain them, it invariably leads to acceleration of intrinstic epigenetic clock.
Telomeres are like this negative counter, it's there but don't touch it, if you do - by trying to 'increase telomere size' - it becomes negative.
That is why the discrepancy between very long lived animals who maintain a certain telomere size, almost frozen - NOT by telomerase but by other means and counter telomere shortening by other ways (better maintenance of the 'rest'/lower DNA damage all around).
while mice have very long telomeres and die in 2 years with much longer ones than humans; telomeres are just one facet.
The Bigger one is the intrinsic epigenetic aging, as it dictates maximal longevity - that depends of the cell 'phenotype/signature'.
It's like saying : ''I am 50 years old, but my body feels 20''...deep down you know you are not 20 anymore, your Signature/Phenotype is much older and you might be VERY healthy, does not change anything about intrinsic epigenetic aging (age 'signature') which is Different that External one/health related one.
I fear that is problem will be something Like really tough to crack open, because SENS or ant other reserach has no way of preventing this hard limit; and could be our death knell, as in all the therapies we want will not avert the intrinsic process from continuing as it does (if that is so LEV is near-nigh impossible, we'll have to be clever because 'god' outwitted us again).
DNA epigenetic aging is one clstrfk to say the least. Let's hope intrinsic epigenetic aging is finally 'mapped', 'hacked' and 'cracked'; in my mind, it is closest to the holy grail of LEV, because a 'age signature/phenotype' (i.e. a 30-year old body 'aged for 30 years' vs a 60-year old body 'age for 60 years' are two different things/biosignatures) determines your biological age and chronological one too.
Just a 2 cents.
PS:
The way i see it,
Both telomere elongation or telomere shortening can accelerate intrinsic DNA epigenetic clock, only 'frozen' 'untouched' telomeres are the ones that create 'quiescence/slowed growth/longevity'.
Telomere shortening -> Accelerates IEA, is seen during early life (developmental growth, children
lose 2KB of telomeres in the space of 3 years...something older humans don't lose so fast, demonstrating immense 'growth' acceleration to 'reach puberty' and demonstrating telomerase a 'pro aging/sexual reproduction hormone activated' element, cell passaged, a baby's IEA is much lower than a teen child, but during the next years this baby will experience IEA advancement - upon approaching teen 'sexual reproduction/puberty' (as seen in the study with later sexual incapability (menopause/andropause, not Caused by reduction of hormones/telomerase but By Increased IEA, the cause; remember, YEARS of aging = IEA advancement = cell passaging, cell passaging is Directly Causal of IEA; sexual/growth accelerate cell passaging; that's almost clear now).
Telomere lenghtening -> Accelerates IEA, because telomerase is a double-edged sword, it's a mitigator of damage but at the same time of promoter of IEA; technically, it's not telomerase/TERT per say, but the cell passaging the mean culprit; telomerase contributes to this cell passaging and in doing so, colocalizes to IEA. When you lengthen telomeres, it's like a 'call' for 'growth' - 'rejuvenvation', as we have seen such as in Liz Parrish CEO Bio Viva; it can rejuvenate you - but not change your IEA, since you increased telomerase/TERT activity; my guess is that, if there is no cell passaging - with TERT present than TERT becomes inert; cell passaging is unconditional to IEA, while TERT is.
Telomere size freezing/(greatly deccelerated telomere shortening but with NO lengthening either)
-> This is 'sweet spot' in between, the telomeres are maintained 'tall enough' but not too tall either, and just 'don't shrink' either, thus 'frozen' there at their size if you will...
Animals that live the longest have a Much Longer preservation of telomeres length Over a Long time, meaning there telomeres DO shrink, but VERY SLOWLY - almost 'frozen'....does, no IEA from no TERT 'need'. These long lived animals, are Slow growth, slow puberty onset (bowhead whales and quahog clams are reproductive only at 30+ years old, while humans are sexual capapble at 9 years old nowawadays with kids growing too fast and 'hormonized' to the max).
I agree 100% with Antonio and Corbin. (And with Cuberat about reaching LEV etc). It's a shame the naysayers get so much publicity with their negativity but you all countered it with a few well-chosen words.
PPS: Senolytics/senescence cell removal/ablation therapies will do nothing much (if any) for maximum lifespan, but will improve health :
''Single-time point analyses
(Fig. 3d) showed that TERT-expressing cells exhibited a linear
relationship between time in culture and the Horvath estimate of
DNAm age (equivalent to a DNAm age of 50 years at 150 days),
whereas in non-TERT cells DNAm age plateaued (equivalent to a
DNAm age of 13 years) in spite of continued proliferation to the
point of replicative senescence. Notably, DNAm age did not
increase in TERT-expressing cells that received regular media
change but were not passaged throughout the entire observation
period of 170 days (right most bar in Fig. 3d). These cells were
not senescent, given that their subsequent passaging resulted in
normal proliferation.''
Replicative senescence is Independent from IEA (longevity), it is much more related to EEA (health).
The fact the replicative senescence can occur in much lower IEA makes a case against it for controlling IEA; it is uncoupled from IEA. And it makes sense, health is EEA, IEA is longevity; thus replicative senescence is related to health not longevity/intrinsic;
''DNAm age plateaued (equivalent to a
DNAm age of 13 years) *in spite of continued proliferation to the
point of replicative senescence*''
''TERT-expressing cells exhibited a linear
relationship between time in culture and the Horvath estimate of
DNAm age (equivalent to a DNAm age of 50 years at 150 days''
It's telling that IEA is acting that way, it's telling us that replicative senescence Can Occur at Very Low intrinsic methylation age (13 vs 50 years old), it all depends on cell passaging and acceleration of it via telomere elongation/telomerase/hTERT activation while cells passage.
It's also telling us Querceting/dasatinib/senolytics/p16 ApoptoSENS or other senoyltics therapies will not do much on maximal longevity, but will improve 'Mean/average' lifespan by health improvement (they will improve EEA; EEA does not control maximal lifespan (only health state), that is IEA).
What I can also deduce from these studies, is that damage/inflammation is OverRated (remember DNA damage causing replicative senescence will not lead to necessarily faster IEA (in fact, it can be lower yet the damage/inflammation is higher (think, like a child being sick...IEA is very low but diseade inflammation causes higher EEA in child. I.e. the child is Still Younger Than You (epibiologically by IEA signature phenotype), despite more damage/inflammation and in 'diseasd state'), IEA is Very Special and thing of its own), it's important, but what Is More, is cell passaging and dynamics/cell cycling/proliferation - which Directly Acts on the IEA, thus on our Intrinsic DNA methyl clock and thus, maximal specie longevity.
It's really not that complex CANanonymity, longer telomeres just mean cells can divide more times so have more opportunity to acquire epigenetic alterations. And those marks used by Horvath in his clock have yet to show any deleterious effect.
As for health spanners, they are useful as a bridge to the public but don't take them too seriously.
Longer telomeres are able to form the loop structure that contributes to genomic stability and epigenetic stability via its influence on gene expression and chromatin. Telomeres are very important for those two things and are closely connected to the structural proteins Lamins which decline with age and are also responsible for some progeric conditions. This leads back to DNA damage and the resulting epigenetic changes being king of the hill.
Also, just healthspan is absolutely not the goal and we try to avoid using the word too much at LEAF and certainly do not present this as the only worthy goal. Certainly, it is publically palatable but we prefer "healthy longer lives" over such limited ideas.
In light of the above discussion, let's assume the senolitics don't increase the Max LS. Just the health span and the median longevity. What's the life span definition as of now? Do we say 120 something as the maximum confirmed LS, or we are talking about the life expectancy?
Those values are quite different and by adding health to a 80 years old you will inevitably increase the life expectancy.
It is not that the we will have this magical treatment that keeps you like 25 until 80 and then you abruptly drop dead. But that's what the year of healthpsan vs lifespan imply if brought ad absurdum..
@Cuberat imo senolytics will more likely impact healthspan, though we could see more people living past 100. remember that senolytics are one part of the puzzle, annd i dont expect a significant LE increase from senolytics alone
@Mark
Hi Mark! Thanks for that. Just a 2 cents. It's true, but yet at the same time, it's the problem, it's not a solution; if telomeres being taller can allow more epigenetic alterations simply because of a much longer period of time - to let them happen; then, it means epigenetic alterations are Truly the main element associated with intrinsic aging. And, it's important to remember that telomerase increases telomere size, while increasing the intrinsic epigenetic clock (not the extrinsic one, as TERT only colocalizes too IEA on the chromosome); it's clearly a 'rigged' game we lose at. Taller telomeres do mean health improvement/'rejuvenation' if you will, but not instrinsic clock rejuvenation, but it ages it instead. That's becuase this is a cell passaging dynamic happening, telomerase happens during cell passaging and this contributes to advancement of IEA.
Let's say we take all the SENS therapies, we would see telomere shortening rate decceleration or a 'rejuvenation' towards 'taller telomere' boosted up againg; if telomerase is present; but SENS with WILT intends to do whole-body interdiction of lenghting of telomeres (by blocking telomerase mostly, to avert cancer tumors highjacking it like they do or use ALT telomere lengthening). And, it's also, Very Telling that IEA was associated with colorectal cancer advancement; Cancer = accelerated IEA, because cancer is directly tied to 'cell passaging' and abuses telomerase for its own end (to 'freeze' around the 2KB region in its telomeres and never go below; thus prolliferate forever/immortalize; thanks to telomerase or ALT telomere recombination/fusion maintaining telomere size to not shrink -while at the same time, we Know that Telomerase/ALT will cause IEAA (acceleration)). Also, it's not surprising, that cancer itself is all about cell 'proliferation/unabated uncontrolled mitosis/infinite replicative potential/immortalization', and, especially, Growth. Cancer is all about growth, growing tumors, growing cell size, cell growth, cell cycling acceleration, etc. And, why, it would influence negatively IEA.
The clear 'signals' (epigenetic signals) sent by Cancerous cells is in direct Talk with IEA.
''Trade off between Telomeres Size and IEA''.
@Steve
Hi Steve! Thanks for that., Exactly, telomere preservation and lengtening can bring health improvement and stability - at the cost/tradeoff of IEA biosignature/phenotypic aging.
Yes, prelamin/lamin a increase in HGPS progeria, which causes progerin to be produced, and thus messes up chromosome function. But, there is a but, progeria as seen in HGPS people who live 15 years is a 'form' of 'acccelerated replicative senescence' (as seen in SAMP8 mice, or mutator mice), but is 'different' than 'regular' 'cell passaging' over a full non-progeric healthy human lifespan.
The epigenetic dynamic of progeric vs healthy people is different. The former is more dependent of replicative senescence, while the later is more dependent of telomeres dynamic via telomerase/shelterin proteins and, the cell passaging process; the main contributor to IEA.
Just a 2 cents.
@Cuberat
Hi Cuberat! Good question, I think the lifespan definition is what vague, average lifespan definition is 'mean/average lifespan' but not Maximal lifespan. Yes, 120-130, is roughly the IEA limit for humans, thus maximum 'known' confirmed LS so far. Life expectancy is what you call how long people live in a country, like northern countries it is about 80 years old give or take. It has greatly risen in most undevelopped countries thanks to, finally, getting sanitary conditions and more advanced modern medical help. Life expentancy, is what you expect humans to live, it is mostly the 'average/mean' lifespan, 80 years is roughly the average of 1st-world countries. But, that is not the maximum and is different, just think of it is like 'the 'mean/average' lifespan' - but Not the longest Possible/the Maximum possible for human (122-130).
Exactly, adding health to a 80 year old will allow the EEA to be altered (that 80 year old one), and thus, allow the 80 year old person to Have a Chance to reach the 122-130 - but once that happens, the Full IEA kicks in, as in, it is a stochastic intrinsic epigenetic process - your 122 year old body is IEA epigenetical 'aged' 122. Your chances of dying before 130 are thousand folds higher then, due to IEA 'signature/phenotype' of a 122 year old person (whom had 122 years of 'cell passaging' and telomerase 'work'; as Mark said, epigenetics alteration over 122 years; that's a long time 'to change the whole thing'; and we know how changes it : it changes towards IEA 'aging' (more), thus death at one point).
As Scott said, senolytics will improve health (100% sure, as it does in p-16 senescent cell ablated mice, by reducing SASP/inflammation from said senescent cells - but that is All EEA domain, not IEA; thus health domain, not the domain of longevity/maximal LS).
Just a 2 cents.
I don't think we should be so hard on healthspan people. Attitudes are hard to shift; it's far better to get people thinking about healthspan improvements than just saying that aging is intractable. And every year of healthspan that we get is some fraction of another year that we get in the short term, with that much higher a chance that of surviving long enough for real therapies to hit.
Every year of healthspan also lets people ask "Well, why can't 90 be the new 60? Why can't 100 be the new 60?" Those shifts are important - we can't make everyone immortal if everyone isn't on board.
These sort of articles are an annoyance. No one has clearly demonstrated anything much yet in regard to lifespan extension and already we get hand wringing about it.
Jay is a freak, also he cannot understand very simple engineering. You cannot fix your car speck by speck. Car either can drive or cannot drive -- that is all! You cannot improve (really improve) health span without improving lifespan. And these phrases are very stupid -- "what if senolytics alone do not increase maximum lifespan?" What? Of course, they will not!!!! Because senescent cells and chronic inflammation is only one type of issue from the seven! That is the reason why we have to implement all SENS panel. How stupid human have to be to not understand these basic things?
It needs to be said that many surveys reveal people don't want to live long, particularly given what modern medicine has done to leave seniors in a state of mental confusion, over-drugged, drooling at the mouth, incontinent and in a wheelchair. That is why, when I talk about super-longevity, people almost invariably say: "Oh, I never want to live that long!"
Somehow, there is a disconnect. In the public's mind, lifespan is separate from health span. But you aren't likely to live long and still incur all the maladies of aging (cataracts, memory loss, withering bone and muscle) if a technology is tapped that truly addresses aging. The universal answer to the question: "How long do you want to live?" is "as long as I am healthy."
However, the public has a different view --- a mirror view. They want to look young in the mirror (no wrinkles, thick hair, smooth skin, Viagra-baby!). These are vain pursuits. They want eternal youth, not eternal life. There is a fable of someone who asked a Greek god for eternal life and forgot to ask for eternal youth and looked so old she wanted to die.
Once past the issue of health span to accompany lifespan, the next barrier to acceptance of super longevity is to answer the question: "Who will pay for my retirement check?" It won't be government as the Social Security (and Medicare) trust funds only have IOUs (US Treasury notes) in them. Olshansky claims 7 more years of independent living would avert a collapse of these retirement funds (aka "longevity dividend").
Once past that objection to longevity, many wonder if they will contribute to overpopulation. But in developed countries, population size is in decline. Women only have 2 babies.
There are a lot of barriers to overcome to get any technology accepted by the public.
Bill Sardi
@Bill,
To respond to the 2nd half of your comment, the answer is robotics, AI, and automation with the result being BUI (Basic Universal Income).
I can foresee (hmm, I sound like Ray K.) when robots will replace workers over the next 2 decades. Then the government will (or should) step in and tax companies a certain amount for each person that gets replaced by a robot. This tax goes to the government who in turn provides it to the general public in the form of BUI.
re: 'vain pursuits'
Lookism is pervasive in society; to some degree it is instinctive - we prefer to look at healthy people generally and sexually attractive people in particular. Further, most find the appearance of both sickness and extreme old age frightening (note how the ghouls in horror movies have the look of extreme old age - and yet don't lack physical strength and stamina) and this is largely beyond conscious control. Of course, it is within our control to treat everyone with dignity and fairness; unfortunately, not everyone does. I read recently of a man who underwent a face transplant because he was disfigured in a hunting accident; he described thoughts of suicide due to the types of reactions he experienced. Most people would find such ostracization unbearable and I do think the elderly become isolated at least in part because they subconsciously sense the fear their appearance provokes in others, even if those others are unaware of the subtle cues they are giving off.
As I & others have pointed out in previous discussions, rejuvenation therapies will largely address the appearance of age as much as aging associated health issues since the underlying causal mechanisms are the same. If more people can be motivated to come to the longevity / rejuvenation technology movement table because of 'vanity' then why not welcome them.
As for sexual attractiveness, many (most?) people find lack of sex seriously diminishing to their quality of life and the inability to find partners can lead to depression. There's nothing wrong with enjoying an active sex life or of ranking sex high on the list of 'Things Without Which Life is Meaningless' - which is a different list for everyone, obviously. Boggle is on mine; I don't expect anyone to understand that, but it's my list - no one else's.
S. Jay Olshansky: For my part, I'm not sure that it much matters whether the focus is on healthy lifespan or overall lifespan, as a comparatively simple strategy that should produce large gains in lifespan does in fact exist, and is described in detail in the SENS rejuvenation research proposals. The strategy is to identify and repair the known forms of cell and tissue damage that cause aging, that arise as a side-effect of the normal operation of metabolism and have no deeper cause themselves. The best analogy is rust in a complex metal structure; rust is very simple, but the progression of decay as the structure falls apart will be as complicated as its shape. Aging has simple causes, it is exactly an accumulation of damage, but it appears complex in its progression because cellular biology and its reactions to damage are complex.
4albearth: Actually it is an accumulation of waste that soon damage the structure and it can be prevented by waste management, it doesn't even need an external intervention in order to repair itself and prevent further damage. Our body is complete with processes that need activation when its required to act upon. The only time it cannot do its job is when a person had done something that interferes with the repair process.
I suggest that we should focus on staying young and healthy by preventing the accumulation of waste inside our body that will destroy us in the long run and let scientist do the rest if we are unable to do it ourselves.
Practice Waste-Management and you will soon find out that it will keep you young and healthy.
Late PS:
I am now convinced and 100% believing that changes on the DNA decorum are what determine specie Total longevity, not necessarily health though, but maximal specie lifespan. The cell milieu is the environment that can deccelerate or accelerate these changes on the DNA methylome. Excess damages speed up the epigenetic alterations that happen with age.
One study proved that there is a correlation between DNA methylation/epigenetic clock and longevity, by comparing rate of methylation position changes in Cytosines (CpG islands, and non-CgG islands) over a lifetime, in various mammals of extremely varying longevity (mouse, dog, humpback whale, human); the striking feature was that this was also visible in non-mammals too - in nearly any animal. Even more so, inter species: they compared a small datschung dog (lives around 15 years) vs a big labrador dog (lives 8-10 years), there was much faster methylation position changes in the labrador's CgGs/non-CpGs loci.
This demonstrated that accelerated aging equals accelerated methylation position changes, with accompanying 'global DNA demethylation' in non-CpG islands (while there is 'hypermethylation in CpG islands, in essence antagonistic pleiotropic detrimental or compensatory genes are hypermethylated with age - to counter aging; while in longevity, there is a clear quiescence/gene silencing maintenance.
The LESS epigenetic alterations the LESS the aging advances. More epigenetic alterations = advancement of DNAm clock. Global DNA demethylation (hypomethylation) leads to 'activation' of inflammatory pathways and dysfunction (which leads to More Demethylation in a vicious circle - to the end), while certain specific locis get 'hypermethylated' mainly the bad ones that accelerate ROS production and oxidative damage (p16/p53/p21/TNF-a/IL-6/CRP.. to counter tumorigenesis via upregulated immune system inflammatory processes), and create statewide inflammation (contributing to the 'diseases' of age).
There is a clear inverse correlation between mouse and human, and you can see 'graded' in between values for 'in-between' living mammals (naked mole rats, dogs, cows, etc..), demonstrating that epigenetic drifting and epigenetic DNA methylation clock determines maximal longevity in mammals.
The bio signature/phenotype supercedes most everything, it is what determines the longevity possible.
Damages determine longevity too, but there is a whole 'spectrum' wide of damages to be able to increase lifespan Above Maximal one - while DNA methylation clock is much more powerful in that sense - since it equals to the damages; but is far easier to 'pin down' than a thousand different types of damages to be repaired in unison. Thus, far more Pleiotropic-wise than trying to fix all damages (if one gene can affect so many, then it is a better target (smarter) than trying to fix all the downstream damages, which is very hard (if near impossible).
One study recently verified J-haplogroup methylation vs other haplogroup, it showed something interesting, we don't age all at the same speed (we knew that) but epigenetic DNA clock is behind this...another studies showed that African descent people had lower intrinsic epigenetic aging clock but higher extrinsic one, while Caucasian had higher one but lower extrinsic one (this may be due to privilege/access to services thus lower mortality/better health by external access to health care), while Hispanics/Native Aboriginals were in between intrinsic and faster extrinsic. Han Asians, were somewhat comparable but lower intrinsic. Again, showing if you live in poverty/hunger it affects your extrinsic one; while the intrinsic one is birth acquired. My take as to why the Caucasian one would be faster than African is because Albinism/Caucasianism is by itself a product of long term adaptation to absence of sunlight UV rays (during Africa to Europe Migration over 65,000 years since late cave age) in high latitude (northern countries) of Earth. This affected melanogenesis, with albinism being the first mutation visible with that, and many studies have shown that albinism is fraught with deleterious DNA mutations, such as absence of pigment in the skin, in the eyes, blood platelets changes, overal just more unstable genetic (this was demonstrated in Siberian White Tigers, whom lost Bengal Tiger melanogenesis (yellow/orange/stripes), they have blue eyes and white fur (no melanin), and are far more with congenital birth defects then Bengal Tigers are, and die younger too). It is not a surprise, this melanin mechanism is protective of skin but not just that, it orcherstrates many Dna methylation changes wich improve DNA stability (hence, why African Blacks (by melanin production) have lower intrinsic DNa methylation aging rate). It's strange because the longest lived woman was Jeanne Calment, a Caucasian, yet another woman (here) lived to 120 (just 2 years shy of Jeanne, making one of the long lived woman, next to Jeanne and non-Caucasian) and she was Black African descent Haitian.
To comeback to the first point, human ethny J-haplogroups had Higher methylations than non-J groups, they had Lower ATP levels, lower ROS production at Complex I in mitochondria. And they were Younger by 8 years withtheir DNE epigenetic clock than non-J groups (whom were 8 years older, had higher mtROS and higher ATP levels). This also concords with supercentenarian/centenarian/nonagerians whom Also had 8 years of epigenetic age Less than rest of population. Showing us that your ethnical background affects your epigenetic DNA clock aging rate, and also if you inherited centenarian family genetic.
What's more is that progeric diseases like Werner Syndrome (50 years), HGPS (15 years), etc, show a clear gradation in terms of DNA epigenetic demethylation; just like mice vs humans, mice had 40-times more DNA methylation CpG methyl position changes than humans, they live 40 times less (2 vs 80 years).
Same thing for 5-mC (5-methylcytosine levels in CpG, mice lose them 40 times quicker than humans', showing many times faster Global DNA demethylation with age in mice).
Animals that live the longest, have the least 'alterations' epigenetically, and maintain 'non-alteration', 'Gene Silencing'. Which means a 'quiescent state' where there is Very Sloow Growth and retarded Changes/alterations over time, which, then, Allows a Very Long Lifespan.
Fixing Damages may (or may not) allow LEV to happen, because if DNA epigenetic clock does not resolve itself upon repair of damage then LEV could not happen, since the clock would not allow it (as cell DNA decorum 'under Methylation control' imposed limit). iPSCs whom are reprogrammed are not 100% back to 'ebryonic' state, they really are a 'different' thing, yet studies determined that their epigenetic DNA methylation age was 0. But, their signature was Not the same as Embryonic stem cells either, meaning these reprogrammed iPSCs had no damage - but were 'Adult', by epi 'memory signature', they were not TRUE embryonic state, they were 'in disguise' 'Adult' cells that behaved 'like 'immature' adults; but STill Adult cells nonetheless.
This is the same thing with studies that reprogrammed centenarians fibroblast cells back to embryonic state. Their cells were now 0 years old by DNAm clock, but were not True embryonic state, they were 'Adult' cells 'playing/disguised as immature' cells. The studies determined that the reprogramming had negative 'residual' effect - you could not 'erase' the Memory 'signature' that an 'Adult' cell had - it was Adult, and upon repgroammation (with OCT/SOX/NANOG YAMANAK FACTORS) - it Stayed adult - but reverted to 'immature state' - As Adult cell.
This demonstrates that damages can be completely reversed by the power of epigenetic reprogramming, but that epigenetic signature can be simply 'Reverted' and the call Exactly Back to Original Young Signature. That is not what the studies showed, it seems 'rejuvenated' 'Adult' cells are younger yes - but still 'adult' cells. How much will this affect aging is hard to say, but we could see deleterious effects from this : think, like Dollie the sheep, she was a clone, and there were more defects with her being a 'clone of a clone' could enter 'errors' and thus cause mutations to happen faster/aging faster.
When you try to reprogramm or clone a 'source' it can be 'worse' then next copy...because it'S still the source but with a different 'make up' but still with all its 'baggage'. 'In disguise'.
Just a 2 cents.
@CANanonymity you post to much misinformation. You are right that at the beginning there were poor quality iPSCs but today there are some techniques that able to generate very high quality iPSCs that are identical to ESCs and pass all the stringent tests. The thing that was with dolly was totaly different, they made her with a different method, it was nuclear transfer into an oocyte and they all know it wasn't very efficient reprogramming. I am a virology phd student at jerusalem hebrew university and there are some researchers here that say that the epigenetic markers are the same for a true iPSC an an ESC.
"As for sexual attractiveness, many (most?) people find lack of sex seriously diminishing to their quality of life and the inability to find partners can lead to depression. There's nothing wrong with enjoying an active sex life or of ranking sex high on the list of 'Things Without Which Life is Meaningless' - which is a different list for everyone, obviously. Boggle is on mine; I don't expect anyone to understand that, but it's my list - no one else's."
If glucosepane breakers can return (to some extent) breasts to a youthful appearance, it will be a huge bussiness, much more so than senolytics.
While AGE breakers should combat stiffness, I have doubts that they will fully restore elasticity and youthful structure of the ECM. I hope my concerns are unfounded as that will mean less than full rejuvenation of both the skin and the cardiovascular system; plastic surgeons will still have their business in breast lifts and scrotoplasties, and cardiologists will have plenty of customers, also.