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Effective Therapies to Extend Healthy Life May Well be Widely Available for a Decade or More in Advance of Definitive Proof

Five years from now, it will be possible to take a trip overseas to have most of the senescent cells that have built up in your tissues cleared away via some form of drug or gene therapy treatment. That will reduce your risk of suffering most age-related diseases, and in fact make you measurably younger - it is a narrow form of rejuvenation, targeting just one of the various forms of cell and tissue damage that cause aging, age-related disease, and ultimately death. I say five years and mean it. If both of the present senescent cell clearance startup companies Oisin Biotechnologies and UNITY Biotechnology fail rather than succeed, and it is worth noting that the Oisin founders have a therapy that actually works in animal studies, while drugs and other approaches have also been shown to both clear senescent cells and extend life in mice, then there will be other attempts soon thereafter. The basic science of senescent cell clearance is completely open, and anyone can join in - in fact the successful crowdfunding of the first Major Mouse Testing Program study earlier this year was exactly that, citizen scientists joining in to advance the state of the art in this field.

Five years from now, however, there will be no definitive proof that senescent cell clearance extends life in humans, nor that it reduces risk of age-related disease in our species over the longer term. There will no doubt be a few more studies in mice showing life extension. There will be initial human evidence that clearance of senescent cells causes short-term improvements in technical biomarkers of aging such as DNA methylation patterns, or more easily assessed items such as skin condition - given how much of the skin in old people is made up of senescent cells - or markers of chronic inflammation. These are all compelling reasons to undertake the treatment, but if you want definite proof of life extension you'll have to wait a decade or more beyond the point of first availability, as that is about as long as it takes to put together and run academic studies that make a decent stab at quantifying effects on mortality in old people.

Uncertainty is the state of affairs when considering the effects of potentially life-extending therapies on human life span. Consider the practice of calorie restriction, for example, where theory suggests the likely outcome is a few extra years, but certainly not a large number of extra years or else it would be very apparent in epidemiological data. I think that an enterprising individual could, given a good relationship with the Calorie Restriction Society, put together a 20-year or 40-year study to that would - in theory - produce a decent set of data on practitioners and outcomes in the wild. It won't happen, most likely, because for one the funding isn't there for such a study, and secondly we'll be well into the era of widely available rejuvenation therapies along the way. Those calorie restriction practitioners will be taking advantage of treatments to repair the causes of aging just like everyone else.

Further, consider the possible effects of bisphosphonate treatment. There is some suggestion that this could add five years to life expectancy, a huge effect to go otherwise unnoticed for a treatment that quite a lot of people undergo in old age - but that may be exactly what has happened, for all we know. There is little work on replication or investigation, sadly. I point this out as an example of the degree to which uncertainty can and does exist for human data, as well as just how hard and expensive it is to dispel. It would take a large study, a lot of work, and waiting for a decade or so to figure out whether this bisphosphonate effect is real.

Now, consider that five years of additional life is not so far off a realistic expectation for the first prototype of any SENS-style rejuvenation therapy, such as senescent cell clearance, that repairs just one of the forms of damage that cause aging. Fixing one thing only gets you so far, as all the other forms of damage will still, on their own, kill you. Aubrey de Grey of the SENS Research Foundation believes that only small gains in overall life span are possible without addressing all of the causes of aging. This is a position well supported by statistical evidence for what would happen if, say, all cardiovascular disease or all cancer was eliminated without affecting other age-related disease. Only a few years of life expectancy would be gained in either of those cases. Arguments against that position run along the lines of suggesting that any repair of damage should produce incremental increases in life span, with reference to reliability theory, or that since all forms of damage and disease interact with one another, removing one will tend to slow the others. But we really won't know for sure until these therapies are out there in use and data is being gathered. You can only go so far in mice, especially given that their life spans are very much more plastic in response to circumstances than ours.

The reason I point out all of this is to note that the next couple of decades are going to be an increasingly confusing time for people who want to purchase elective therapies to extend healthy life. Things that actually work to a significant degree are going to be available alongside increasingly effective stem cell therapies and the same old garbage from the "anti-aging" marketplace that does absolutely nothing but part fools from their money. There will be infinite shades of grey between all of those things. You only have to look at the opportunists selling supposed longevity-enhancing supplements today based on calorie restriction mimetic research, and the articles in which that research is presented as equivalent and equal to SENS rejuvenation research approaches such as clearing senescent cells, to see how this is going to go. To navigate this near future market, for the decade or two it will take for the approaches that actually work to definitively prove their worth in human studies, you must understand more of the underlying science. You must be able to explain to yourself why damage repair approaches like those of the SENS portfolio are more likely to be effective than calorie restriction mimetic supplements - in short, your participation in the market will be guided by your take on the science. This is far from an academic exercise; time matters greatly.

Comments

Hi ! Nice text.

I'm looking forward to them too. I feel like it's another project that must not be forgotten : you can't just go about your everyday life and forget it
all; you have to sort of 'want to', want to keep your health, want to live long(er), want to keep 'learning' 'keep posted/updated' on the science and
whatever's next. But, I believe people sort of give up half-way because of the length of time (snail pace progress); even if 5 years is not such a long wait
for senescence clearance or Bioviva telomerase therapy. It's like it never seems to 'be within reach', as such people think it's like mirage oasis
right in the middle of desert; as you approach it, it keeps on 'getting farther' and as you walk some more towards it, it moves away some more. You now realize
the (optical and figurative) illusion 'is real'. A bit like when you look in your car mirror 'Objects appear closer than they are' (here, 'Rejuvenation
Therapies Appear Closer Than They Are'). People can't continue watching in the side car mirror, they want to turn their head and see the therapy right
behind; alas it's not there, it's farther behind.

''Five years from now, however, there will be no definitive proof that senescent cell clearance extends life in humans, nor that it
reduces risk of age-related disease in our species over the longer term. There ''

Exactly. I still think there will have been improvements but from your website started back a long ago; you started this a while ago and
stil talking about it; thus it shows that things move on ultra slowmo; and SENS was already something in the making in early 2000.
16 years later - 16...count 'em...oh well..I'm guessing it'll take double that to get 1 or 2 strong SENS therapies (32 years). I know that guessing is useless
and things change fast sometimes but lately it hasn't been the case - for aging I mean. Not for the rest (like organoid creation, health improvements...but aging, ?? nope, just rehash calorie restriction
studies one after another like some crazy person doing the same thing over and over. SENS is doing something about it, altough to be honest from the last post...it doesn't look good, that will need billions of dollars
to make SENS, ouch. 100 millions of dollars for 10 years won't cut it for 7 therapies. It will amounts to so much cash...how can crowdfunding ever help that. It's impossible, unless we convinced every human on earth (which so far has been impossible since little people believe in SENS).
Billionaires are the only solution, and even then as was said, R&D in diseases approaches 500 - Billion dollars and the total 2 trillion on health over many years. I don't know how AdG will get this astronomical amounts of money over the decades and if he will still we be alive)é

So what can we do now ? Not much but continue marching on.

''Uncertainty is the state of affairs when considering the effects of potentially life-extending therapies on human life span. Consider the practice of calorie restriction, for example, where theory suggests the likely outcome is a few extra years, but certainly not a large number of extra years or else it would be very apparent in epidemiological data.''

Very true. I think Calorie Restriction won't make miracles but it's definitely good.
What we have to do is concentrate on the people that reach to a 100, 110, 120. Those centenerians, though some are outliers and do things
that kill us non-centenarian in the family, but some of them do things that we can do and give us a chance to reach that age - without any SENS, if it
never concretize seriously (to reverse aging truly) in the next 50 years (most of us are 20-50 years old now, our (unborn or young) children are more likely to be the recepient of these
then-technologies (nanorobots ??...still scifi, if AdG can make structured nanorobots repair everything and remove lipofuscin with targeted bacterial degrading enzymes; it will help a lot towards rejuvenation; but I have reservation one man can make mirages/miracles in less than 30 years;
it's a ultra-large team effort).

Nutrition is one thing (not just talking about calorie count restriction) but nutrional composition is a great enhancer of lifespan, people should aim that but changing nutrient density/composition in choice of foods.
They say food is medecine, there is some truth in this depending on nutrient composition. We just have to look a studies like methionine restriction which increase lifespan of mice and show that nutrition/nutrient composition has a strong effect on lifespan - more than restricting calories (which sometimes is erroneous and the effect is protein restriction the effector).

Interesting times.

Posted by: CANanonymity at July 21st, 2016 8:53 PM

Do you know a paper that proves that at least 10 years are required? Can't it be, say, 3 years with a big enough population size? Which are the numbers?

Posted by: Antonio at July 22nd, 2016 2:42 AM

I'm only a layperson, but I'm still very curious about how Oisin's 'gene therapy' manages to reach every cell in the body while other attempts at in vivo gene therapy only seem to achieve expression in a small percentage of cells?

I get the feeling that comprehensive in vivo gene therapy is still one of the major technological breakthroughs necessary to make the SENS approach possible.

Posted by: Jim at July 22nd, 2016 4:24 AM

Jim, it seeks out cells expressing P16 and locks onto them.

Posted by: Steve Hill at July 22nd, 2016 5:49 AM

Posted by: Jim at July 22nd, 2016 4:24 AM: I get the feeling that comprehensive in vivo gene therapy is still one of the major technological breakthroughs necessary to make the SENS approach possible.

Oh, certainly - we've always emphasized that. Before SENS Research Foundation was formed - even before it existed as an informal division within the Methuselah Foundation - back when the strongest source of information on comprehensive rejuvenation biotechnology was Dr. de Grey's personal website at Cambridge, we've always had a whole page dedicated to the importance of gene therapy as a enabling technology for rejuvenation biotechnology. See also my comment here:

The budget [laid out for robust mouse rejuvenation within a decade] was intended to include only core work on rejuvenation biotechnology: it assumed the ongoing progress in life sciences generally, including above all things like gene therapy, which is a robustly-supported area of research whose medical value is very widely accepted in biomedical research and only modestly controversial in public discourse. The original timescales therefore essentially assumed the emergence of robust gene therapy and other tools of widespread biomedical utility out of general biomedical research

Posted by: Antonio at July 22nd, 2016 2:42 AM: Do you know a paper that proves that at least 10 years are required? Can't it be, say, 3 years with a big enough population size? Which are the numbers?

Even to demonstrate a lower death rate from, say, heart disease in 3 years (which would be the easiest outcome to pick up following comprehensive rejuvenation) seems to require an implausibly-large controlled trial, granted the many hundreds required for a very expensive trial to show lower mortality rates from statins within 5-7 years in secondary prevention trials with persons who have already had a heart attack or other major adverse cardiovascular event (MACE) - a result that was still in dispute many years after the first trial reported it. It took larger and longer trials, and a lot more argument and mutual dissection of mathematics and methods, to really make a convincing case that they also work in primary prevention in people at high cardiovascular risk but who have not yet had MACE. And it's a lot easier to run such a trial when your therapy is one daily pill than a suite of multiple rejuvenation biotechnologies with less-than-convenient methods of administration and performed on different administration schedules, etc.

To really show rejuvenation (as opposed to such individual outcomes) you need to demonstrate the shifting to the right of the entire mortality curve: absent a complete lifespan study, this at minimum requires a time period greater than doubling of the population rate of mortality, which in humans is 7-8 years.

Posted by: Michael at July 22nd, 2016 6:29 AM

How does it lock onto them? P16 is a protein expressed on the surface of cells? Or is some fragment of it expressed on the HLA?

Posted by: jim at July 22nd, 2016 6:40 AM

Thanks for the reply, Michael!

Posted by: Antonio at July 22nd, 2016 8:42 AM

Just to clarify my own comment: while we shorthand that Oisín's system is "gene therapy," it's a non-integrating construct delivered via liposomes: this is a much less challenging method of delivery than "gene therapy" in the usual sense of inserting new genes into the host cell's genome, both in efficacy and especially in safety terms. I was making a more general point about the need for gene therapy as a delivery system for other rejuvenation biotechnologies, such as installing "backup copies" of mutated mitochondrial genes in the nucleus or the very long-term and most challenging last stages of making the body invulnerable to cancer.

And, as Reason says, Oisín's system triggers the self-destruction of senescent cells based on their expression of the p16 gene, not detecting the presence of the p16 protein.

Posted by: Michael at July 22nd, 2016 11:36 AM

Ok, why don't they use such an approach to attack cancer cells with a mutated RAS or p53 gene? I've read that this is 'undrugable' with small molecules, and that cancer researchers were excited to be able to target it with a new class of drugs that targets proteins for destruction (can't remember what they are called).

Sorry for asking so many pointed questions.

Posted by: Jim at July 23rd, 2016 3:35 AM

@Jim: As a technology platform, Oisin's approach has very broad uses. Like all technology platforms, you have to get it out there and prove utility for a first use in order to gain the resources to do other things with it. For my money, cancer isn't the most interesting next target, but rather selective destruction of various types of immune cell.

Posted by: Reason at July 23rd, 2016 8:57 AM

@Michael how does the system get around the P16 issue in say B-Cells which express P16 in increasing levels as they age?

Posted by: Steve Hill at July 23rd, 2016 12:33 PM

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