A Summary of the NIA Interventions Testing Program
The NIA Interventions Testing Program (ITP) is a fairly old-school effort to rigorously test all the plausible claims of modestly slowed aging in mice via pharmaceuticals, dietary supplements, and environmental factors like calorie restriction. For those of us more interested in outright rejuvenation through damage repair after the SENS model, rather than merely slowing aging a little, I think there still a number of things worth learning from the ITP results to date. For example, firstly, that almost all claims of slowed aging in mice due to supplements and drugs made in past years were artifacts or otherwise erroneous results, and vanish when evaluated with greater rigor. That suggests that any result of around 10% life extension in mice should probably be taken with a grain of salt, given that the ITP researchers have observed variance in the life spans of control mice raised in identical environments at different study sites. Secondly, that it is very hard to evaluate small differences in aging and life span. This is a part of the larger point I try to make on efforts to slow aging: that for a number of reasons it is more expensive and more challenging than attempts to produce rejuvenation by reverting the established differences between old and young tissues, such as accumulations of metabolic waste, senescent cells, and other forms of molecular damage. Rejuvenation therapies, when they work, should reliably result in larger differences in life span - there should be absolutely no ambiguity at all about the outcome.
The Interventions Testing Program (ITP) was established by the National Institute on Aging (NIA) to investigate the potential of dietary interventions to promote healthy aging. The ITP uses a four-way cross genetically heterogeneous mouse model (UM-HET3) to reduce the impact of strain-specific characteristics on outcomes. Lifespan tests are done in parallel, using the same protocol, at three independent sites to increase robustness of the findings. Population sizes are large enough that the protocol will detect a 10% change in mean lifespan, in either sex, with 80% power, pooling data from as few as two sites. Standard operating procedures were designed to maintain as much consistency as possible among the three sites, including caging, bedding, food, and light/dark cycles. Interventions for testing are proposed by the research community through an annual call-for-proposals, and proposed compounds have ranged from drugs and dietary supplements to micronutrients and metabolic intermediates.
Before the ITP embarks on testing a compound, pilot studies are done to maximize the chances of a successful test. Goals of the pilot studies include demonstrating that the compound is stable in food and that it is uniformly mixed in the food, determining blood levels after short-term treatment (bioavailability), showing evidence of an effect from the short-term treatment (bioactivity), and in some cases, testing for toxicity. The testing of rapamycin is a good case-in-point for analyzing stability of the compound in the food. Pilot analysis showed that about 85% of the rapamycin was degraded by the food preparation process, leading to the use of microencapsulation to deliver stable doses of the compound in food.
The list of all compounds tested by the ITP and in progress is on the ITP website. To date, six compounds have shown significant extension of lifespan: aspirin in males only; rapamycin in males and females (with a greater effect in females); 17αEstradiol in males only; acarbose in males and females (with a greater effect in males); nordihydroguaiaretic acid (NDGA) in males only, and protandim in males only. The positive findings illustrate some important aspects for aging interventions research. The effective interventions appear to include several disparate mechanisms, demonstrating that many cellular pathways might be exploited to influence lifespan and aging. Rapamycin modulates the nutrient-sensing pathways via its interaction with mTOR. Acarbose was anticipated to work as a caloric restriction mimetic due to its ability to reduce the rate of absorption of carbohydrates, but its mechanism of action appears more complex, since caloric restriction results in significant lifespan extension in both male and female UM-HET3 mice, while the effects of acarbose were much larger in males. Aspirin is known for its anti-inflammatory and antioxidant activities, NDGA also has anti-inflammatory and antioxidant activities, 17αEstradiol has neuro-protective properties independent of binding to the estrogen receptor, and protandim activates Nrf2 transcriptional regulator. This diverse group of interventions demonstrates the complex nature of the biology of aging.
Another major surprise is the extent of sex differences in response to the interventions. Four of the six positive interventions only worked in one sex, and the two that had an effect in both sexes showed sex-specific differences in the extent of the effect. Blood levels of a compound sometimes differed between males and females, but that did not always explain the sex difference in lifespan extension. For rapamycin, achieving approximately equivalent blood levels in males and females by treating with different doses did result in similar increases in lifespan. But for NDGA, even at doses giving similar blood levels in males and females, females still did not respond. The ITP's findings illustrate how important it is to examine the effects of interventions in both sexes and suggest that further studies on the mechanism of these sex effects may yield important insights into the underlying biology, and guidance for eventually clinical studies. Multi-site testing protocols also add value to the design because some site-to-site variation is unavoidable even with every effort made to minimize differences between sites. For example, the ITP has consistently found that control male mice at one site weigh less and live longer than the control males at the other two sites, even though each site uses the same food preparations and standardized husbandry. Positive findings replicated in different labs are inherently stronger than a finding from one lab, while disparate findings convey a valuable caution and emphasize the need for replications in other laboratories, other mouse stocks, and other drug doses.
Link: http://www.ebiomedicine.com/article/S2352-3964(16)30554-0/fulltext
anyone considering using the combination of rapamycin & metformin that showed some effects ?
@Michael: The ITP only tests a few interventions each year, given their budgetary limitations, and historically they've focused on single interventions rather than combinational approaches. They're open to proposals, however, so getting a lab and some funding in the same place might work to get them testing combinations:
https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/suggestions-scientists-who-wish-propose-interventions
My bias would be that said funding would be better directed to SENS, of course. I think that the main value of the ITP has already been realized, and that they don't have to continue at this point. That value is to identify that most interventions in the class they focus on are not worth large further investments.
I thought for-sure that there were animal trials (worm, mouse, yeast) which showed X-times life-extension...is that not correct? Were they just not repeatable?
@Eugene: For worms and yeast, yes, up to 1000% life extension via genetic manipulation. For mice, no, the record is still 60-70% via growth hormone receptor knockout. There are numerous other genetic manipulations that extend life in mice to various degrees. But all of that is outside the purview here - the ITP only looks at pharmacological and dietary manipulations.
Hi there,
Just a 2 cent.
I am too share that opinion. I don't understand why there is so much energy, still, being put in these
methods of anti-aging. It has been characterized as mostly a failed avenue. What works in mice is not
very translatable in humans (for a ton of reasons), in general. In general, yes we see similarities,
but the results the differ between mice and humans. Calorie Restriction (which we have been talking for
about 10 years now at least if more) is something, almost mythical, that has now been shown to be
much weaker in humans (as you said, where is the account of someone living 125 years on Calorie
Restriction - nowhere, because it doesn't exist). One recent study did Calorie Restriction (about 40% CR,
mild-to-hard restriction in calories) in old world monkey Rhesus Macaques (that live 30 years)
for a quite a long period (many years) - the results were non-surprising - if slightly : CR did absolutely
nothing on their lifespan and changed squat-all on most of their advancing biological aging parameters.
What it did do is reduce mortality a bit (a good thing, calorie restriction reduces proteasome junk/helps autophagy,
improves redox and inhibits AGEs/crosslink formation by reduced glucose exposure/glycoxidation while getting
enough calorie for energy daily kJ need). Mice results of Huge Lifespan Extension (50%) do not translate at all in
Rhesus Macaques or Humans (which have Far more in common in biology and length of lifespan, being old-world
monkeys while humans are apes descendant like Chimpanzees. Not just some 'other' mammal, but a bipedal mammal.
It's a direct ancestry link and thus the highest probability of result translation). Thus, we can infer
CR only helps human to have a better 'healthy aging' profile rather than be fighting disease as unhealthy aging.
Centenarians show us, and prove us, that aging is complicated than we though as there can be 3 types of
centenarians : Delayers, Escapers and Survivors (I might be in that category since I went through some sh..).
Delayers delay any disease but soon enough disease come, they represent 20-30%. Escapers, the very lucky ones
completely evade/escape most of all diseases altogher - they are 10-20% - the very genetics lucky ones. And then,
the Survivors - my favorite ones, they went through lots of Sh...they had at least one major disease (cardiac problems,
hyper tension (many), osteoporosis, dementia, pneumonia, skin cancer). They are 'unhealthy' centenrians - and reached the age
of 100 - unhealthy. (all centenarians are 'unhealthy', the difference lies in the 'degree' of 'how unhealthy' -
it is 'liveable (no big pain)' or 'unliveable (big pain)) Quality of Life-to-Health'.
If survivors - could reach - a 100 and still suffer greatly, as survivors. It means that damage theory is far
more complex and muddied than we though. My 2 cents is down to susceptibility. How susceptible certain macromolecular DNA elements
are that is what is going on. Some people are 'more susceptible' to 'oxidative stress caused damage' to many types
of epigenetic DNA methylation and gene transcript changes - despite having better redox properties; we are not built (Genetically and bodily) exactly the same way (that's why
you see survivors, escpers and delayers). Also, redox 'allows' someone, such as a survivor, to 'Survive' intense
oxidative challenges which Do damage him/her but the Cell survives and is less susceptible (oxidative-stress resistance theory, NRF2, ARE/EpRE/Heme Oxygenase(Small Heat-Shock Proteins Chaperons who help lipofuscin
lysosome docking/cell cycle dilution and refold undenature/unfolded crucial proteins; this is visible through a reduction of Nucleic Acid oxidation (Telomeres/Telomeric DNA is spared and maintained capped)) creating DNA
single strand breaks and then Double frags. I believe rejuvenation, especially removal of proteasome/autophagic junk (lipofuscin), as power to increase liefspan a bit (not as much as we think sadly, because
CR shows already that damage reduction is moot actually since it does not nothing in Rhesus Macaques yet slows mortality - showing damages are small contribution - where it lies
is in epigenetic part and 'programming' telomere part/cell cycling mechanism (replicative senescence/Hatyflick) which humans are very much bound by).
CR is now done for and will improve your health (a bit and allow you a longer lifespan, depending on 'how' your
body reacts to CR; you may very well not get many benefits from CR or you may reap a bit more depending onyour
phenotype/morphology).
Metformin and Rapamycin, will help for a longer life (controls diabetes, my father takes Metformin daily for T2D
now for many years, was on and off, back on now...it did not change his aging speed - at all...gray hair keep coming, so does skin leathering/thinning and wrinkling (a proof DNA methylation is getting low on global methylation levels and skin telomeres are shortening (reducing cell cycles/closing-in on replicative senescence onset for a proliferative tissue that exhibits high oxidatio such as skin)).
But what it does it control hyper-glucose levels, hyperinsulinemia and glycated hemoglobin (HbA1c) to 'normal'..metformin and rapamycin + CR in mice
equals longer life, in humans longer 'healthiness' thus longer life - but not by that much (as seen with CR doing almost nothing in
Macaques but reducing premature mortality from inflammation in diseases). Aspirin (which is salicylic acid
and salicin extracted from willow tree bark) works about the same way as Rapamycin and does a small CR effect too,
in fact centenarians/elders who took one aspirin here and there and NSAIDs (some developed gastric ulcers on aspirins/Advil)
lived longer and aspirin acts on neuron in a very CR fashion (my guess is it is anti-oxidative (salicylate scavenges ROS), blood thinning, acting on neuron and neuro-endocrine
system (it plays on ghrelin and leptin hormones, just like CR, then on Testosterone and Estrogen, agin like CR through
mTOR and Insulin/IGF/IGF-Receptors in the brain). Aspirin or salicylic acid can save your life from a heart attack
(one aspirin taken during heart attack). Always have some closeby in case something terrible happened. CR is greatly
overrated sadly and its damage reduction is now not as important as we thought - what is, is the susceptibility
of the Cell to said damages - that is far more important - it's why certain animals delay, escape and survive
the Exact same oxidative burden of other (because they are more equipped to deal with that stress, some have
better redox, some have better enzyme, some have better DNA repair and nucleotide lesion repair (BER, NER),
some have more p53 copies, some have less, some are just less susceptible through many 'Adapted' genetic
mechanism.. Just a 2 cent.
PS: I learned recently of an incredible study that advanced a very 'true' thing about telomeres :
Humans have rather short telomeres and lose quite a lot during sexual maturation (coming to adolescence)
and entry to adulthood - then it slows (as metabolism slows down and developmental growths stops 'the downhill
slope of no more 'growth'' of human adulthood until you die). Mice have ultra-long telomeres, yet die very quickly
- that is because they lose 100x time more telomeric DNA per cell cycling and accumulating an inordinate amount
of 'short telomeres' (meaning the genome is totally unstable, speedRate of telomeric DNA base pairs loss is not
the true determinant; what is the amount the rate of - total smallest telomeres count. The more small telomeres
there are in a total of big telomeres, means the person/animal is 'compromised' and disease will come (they
will die prematurely, despite having many 'Tall' telomeres around those shortest ones mixed-in the whole lot).
While people who live longest maintain their telomeres higher and longer - and all of them - long, they do not
accumulate short telomeres as quickly as the others. That means their overall Average Telomere Loss if Averaged
on Every Single Telomere (meaning every telomere is shortening - at the same speed, there is not one 'telomere'
here and there that goes down faster then the others- that is premature mortality and disease/inflammation
gene causing (IL-6, TNF-a, p53/p16 are activated by these small amounts of shortest telomeres).
With that said, the study advanced that humans have a trade-off/bargain, they have Shorter Telomeres (then Mice
who have ultra-long telomeres - yet die much quicker). Mice die much quicker, despite long telomeres,
because they are not equipped to deal with that stress and protect their telomeres (basically their telomeres
become Whack very quickly/unstable, of course they thus die much younger and they lose 100xtimes more telomeric
DNA TTAGGG nucleotide repeats, creating intense nucleic DNA oxidation, fragmentation and DNA SSBs/DSBs).
Why would they have such long telomeres while humans have such small telomeres and live much longer :
because theere an evolutionnary trade-off - you get longevity genes protection of Telomeres and Chromosomes
(Shelterin Telomere Complex Proteins, TRF, TRF2, POT, Ki-67)in humans - thus a longer life; while mice
get a short life by having less-evolved 'telomere-protective adaptive mechanisms'. It's rather ironic,
mice have telomerase, humans don't (in somatic tissues or let's say not much and very little telomere lengthening
except in certain immune cells and germ/sexual stem cells), Telomerase, in a constant fashion on the telomeres,
as what was learned recently increases chromosomal distrubance and disrption (creating chromosome strand breaks)
Mice die of cancer - and have tons of telomerase - humans don't - they post-pone cancer and have better p53
genes. The trade-off of somatic mortal cells (no telomerase or ALT lengtehning) vs immortal mouse cells (telomerase)
is that humans live longer - with shorter telomeres 'who are stable'. Preventing cancer formation.
Cancer forms in shortest telomeres, but increase telomerase presence (creating huge telomeres) compromises the chromosomes
which then - go on to create fusion/ALT/chromosomal breakage - thus cancer. Humans, by their mortality
and telomerase-deficience, block cancer and block 'mice-huge telomeres' problem - but they in return
have to suffer for it :
They become Survivors (centenarians who 'suffer' debility and diseases, because their telomeres are so small
(remember teh shortest telomeres activate a plethora of inflammation inducing genes). It's as if life is this :
You want to live longer - it's not going to happen without certain 'compromise' of aging; you will age 'unhealthily'
because your teloemres will shorten (all in unison at the same rate), but you Will have a longer lifespan.
On in the inverse, you can get a very short life, like a mice, with tall telomeres and everything goes haywire
in a space of 2 years. That mice does not suffer long - it is Killed Quick (by cancer or apoptosis), humans
live long - with their diseases. This study tells us it's a 'compromise' : living long (unhealthy at a certain point,
like 'Stretching it' the most you can) or living short (healthy one day, dead the next).
As for morbidity compression in centenarians, it's very visible and I believe the 'one day live and the next, dead'
is pretty much back during the last years of extreme life (meaning a centenarian can drop dead any day now in the next year or 2).
I don't want to rain on the 'healthy longer and forever' it's possible, but it seems evolution does not favor that.
It favors - survival - Survivors (Centenarian Survivors who survived Misery and Pain - and lived to It, The lucky ones
Escapors and Delayers are Small Percentage). With aging comes many oxidative challenges that Kill you, so of course
you may die but if You Survive you are proof of that : that aging is really an evolutionnary compromise where we can push
so much of ourselves; at a certain point the damage wins it seems and we have 'Survive it' (as seen in survivor centenarians).
So yeah, your quality of life will suck (you may be decrepit and in pain, hurtinng, but still alive - bedridden..some may hate
that and prefer be dead than hurting). It comes down to your will to live vs threshold of pain.
If we put that to living 200-500 years, SENS may not give us that, but if we capable of maintaing our biology to 20
and susceptibility to these diseases - we might have chance - The truth is, there Will Be many Super-5X-Centenarians
who have a very long life (of centuries) that was crippled with diseased, pain and hurting - but They Survived It.
That is Almost an Assurance if we wish to reach over 150 years old. (We just have to look at extremely old aged animals
to realize they are quite 'in pain' over 200 years but 'hanging' on).