I was a college student when I first stumbled upon the “Ending Aging” book by Dr. Aubrey de Grey. I read that book cover to cover but I never got highly enthusiastic about SENS since there were important details which didn’t make sense. The types of damage that humans incur as they age are excellently described by the SENS approach and I applaud the step-by-step approach of extending human lifespan by solving those types of damages one by one.
But I never bought into the idea that you could solve a problem without understanding it first, especially a problem as complex as aging. Besides, there were cases where damage either cleared up or didn’t accumulate much. Such situations didn’t matter when trying to solve aging by SENS and I found that odd.
A first such situation happened in all of us: we were all born young no matter the age of our parents. Somehow the clock is turned back yet almost no one in the gerontology field seems to get inspiration from related fields such as embryology or fetal medicine. For example, during normal human development some cells become senescent and the immune system adequately clears them. The same senescent cells which accumulate with age cause no inflammation in the fetus. That is a system that already works in people at a different age and I have previously described it here.
A second situation happens in those species which do not age. Individuals from these species either prevent certain types of damage from occurring or they are very good at repairing them. The excuse that such species are too different from us never impressed me – penicillin was first developed by a fungus and yet this substance saved countless human lives, mine included.
These are the two reasons for which I am not highly enthusiastic about SENS, although I do appreciate its merits and I think implementing them could change geriatrics for the better.
Like most people, I used to think about aging as an unrelenting process where damage accrues throughout life and it always ends with death. I recently got over this prejudice by reading “The Long Tomorrow” by Dr. Michael Rose shortly after checking his 55 theses on aging on his website . That was a book I read cover to cover in two days. I think it was time well spent since I could finally connect some old dots I didn’t know what to do with, plus it lead me to read two of his other books which I will soon mention.
I read about the evolutionary theory of aging years ago and I immediately shelved it since I didn’t have any idea on how it could be used to solve aging in humans. It didn’t occur to me that you could bring evolution in the lab, play with parameters and create longer-lived model organisms which you could then compare with their normal variants. Breeding such organisms for longevity has already been done in fruit flies and mice. By obtaining such model organisms in the lab you don’t have to guess about which genes or proteins increase lifespan. Not so much a surprise here: there are hundreds of genes involved in aging so there is no single cure for aging or age-related diseases. But evolution already did the hard work for you and now all that is left is to use any omics technologies and reliably direct pharmacological research.
There are two parameters to play with in order to modulate aging in a population:
-first age of reproduction
-last age of reproduction
A gene passes to the next generation only if it helps in creating viable offspring or if it is neutral. The same beneficial gene when young may produce damages later on in the form of aging, a process known as antagonistic pleiotropy.
Here is what you’ll obtain if you shift these two events after many generations:
-an earlier first age of reproduction will lead to a shorter average lifespan
-a later first age of reproduction will lead to a longer average lifespan since natural selection will eliminate those genotypes which do not last long enough to hop to the next generation
-an earlier last age of reproduction will compress the aging phase
-a later last age of reproduction will prolong the aging phase and will postpone the transition from aging to late life
You may wonder what late life is all about. According to the evolutionary theory of aging, senescence is a by-product of natural selection acting the strongest after the first reproduction and diminishing to zero some time after the last reproduction in a set population in a certain environment. But just because the force of natural selection reaches zero, it doesn’t mean that those individuals left will simply die. Instead, they will have reached the late life phase and their mortality rates will tend to stabilize.
A detail that I knew but never took seriously is the decrease of mortality rate in humans when they are very old. Mortality rates in humans stop accelerating at 90 years old and they stabilize around 105 years old. I didn’t think that was important because mortality rates still remain high. But I was wrong since this is a confirmation of the evolutionary theory of aging in humans and this stage of late life was experimentally proved to exist in fruit flies too. Aging is not the exponential increase of mortality rates towards the very end. Aging is just a phase between two periods of stable mortality rates: childhood and late life. These two are different from the phase of aging.
So according to the evolutionary theory of aging, the life of an organism is divided into:
-development – when the force of natural selection is at its highest and the mortality rate is at its lowest except for transition points like birth, hatching etc.
-aging – when the force of natural selection starts diminishing after the first reproduction ending in viable offspring until it reaches zero some time after the last reproduction
-late life – after the force of natural selection reaches zero
-the death spiral (detectable across several adult ages) – it is not known whether this is irreversible or not.
The same theory also explains why organisms with symmetrical asexual reproduction do not age: natural selection will continue to act on the parent as strong as on the offspring. But organisms which reproduce asexually asymmetrically will dilute the waste products in the offspring to the detriment of the parent and the latter will age. I’ve previously wrote a blog post on such polarization here. Lately I found an interesting paper on some yeast which alternates between these two: it ages under stress but it doesn’t age if kept in good conditions.
Basic research is riskier on the short term but it is more useful on the long term. Fruit flies experiments have proved that there is a phase called ‘late life’ when mortality and fertility rates plateau once natural selection doesn’t act anymore some time after the last age of reproduction. The importance of these experiments lies in the proof that damage doesn’t continue to accrue to the very end. It could now be more feasible to stop aging earlier rather than slow down its progression.
The two other books I read which I previously mentioned are “Methuselah flies” and “Does aging stop?” and they summarize many peer-reviewed papers detailing these results. You can find the links in the references section below. An interesting fact I’ve read in “Does aging stop?” is that the late life stage in humans starts so late compared to fruit flies. Dr. Michael Rose’s hypothesis is that this may be due to the invention of agriculture which postponed the last age at which humans reproduced by increasing fertility through abundant calories. The latter also led to an increased population size so it became easier to find mates later in life. According to this hypothesis, returning to a hunter-gatherer lifestyle, particularly after midlife, may make it more likely to reach the late life stage.
I don’t know how many supercentenarians have lived such a lifestyle, if any. The patients who aged well that I saw during the medical residency were quite active and slim. I didn’t notice any of them forgoing bread and cheese but vegetables formed most of their diet and junk food close to none. Since Okinawan centenarians were brought up as a topic in “The Long Tomorrow”, I may add that on that island purple sweet potatoes formed the staple source of carbs unlike the rest of Japan where the equivalent is rice. If dietary advanced glycation end products (dAGEs) matter too in the rate of aging, then even boiled rice is better than baked pastry. In this book, Dr. Rose made an interesting observation that Okinawa was quite isolated and so the infectious risk of such a low-calorie diet was diminished. While visiting Japan last year, I also thought whether their obsessiveness with cleanliness plays a role in achieving the average highest lifespan of any country since infections not only make calorie restriction dangerous, they may also accelerate aging through the damage they cause. Japan is the only country where I loved being outdoors because there was no difference in cleanliness between outside and inside. I wish I could say the same about Bucharest but I’d be a liar if I did that.
All in all, I missed reading a good book like “The Long Tomorrow” and it played out nicely how I ended up reading several other books and papers on aging. But there was one thing I didn’t agree with: the author deplored the lack of anti-aging drugs. Indeed, there are no magic bullets in geriatrics but aging can be ameliorated today by several medications which are prescribed to healthy people. Even if they are not marketed as anti-aging drugs, they decrease mortality rates in the elderly and postpone some aspects of aging.
Here are some examples from clinical experience:
– low-dose aspirin
During the first two trimesters of pregnancy, fetal platelets do not aggregate but they do so more and more efficiently as decades gather one by one. The elderly are prone to thromboses just by being elderly. Aspirin stops platelets from aggregating and low-dose aspirin is prescribed in healthy patients without any clinical sign of thrombosis if they have several risk factors like being obese or smoking. Low-dose aspirin is not a panacea. It has adverse reactions and it is not the solution for every person at any age. But it does prevent many cardiovascular events even in people who never had a heart attack or a stroke.
-vitamin D3 and calcium supplementation in postmenopausal women before osteoporosis sets in. The evidence in preventive fractures is inconclusive though if there is no documented vitamin D3 deficit.
-vaccines
Vaccines are not as efficient in the elderly as they are in the young people but they are still useful in preventing infections. Some of these infections can cause cancer and through vaccination the risk of developing specific types of cancer is lowered. Examples include the hepatitis B vaccine which prevents liver cancer associated with this virus. I would also count antibiotics here since Helicobacter pylori infections that are left untreated – over years and years – may cause gastric cancer. There is no magic bullet in preventing all types of cancer just like there is no magic bullet in preventing aging itself. Both cancer and aging are systemic diseases. Having glioblastoma multiforme is not the same thing as having thyroid cancer. The latter can be surgically removed and the patient will receive synthetic thyroid hormones all his/her life but the same can’t be said about the nightmare of glioblastoma where patients rarely survive more than two years and die in horrible pain.
-as regards delaying or preventing cognitive decline, there is no nootropic drug that can be administered for this purpose. Yet there are two cases of reversible dementia where medication does work: dementia caused by prolonged and severe hypothyroidism and the one caused by vitamin B12 deficiency. At the very least, cholinesterase inhibitors and memantine slow down the cognitive decline in pacients with age-related dementia.
Apart from the anti-aging clinical examples above which may benefit individuals, humans as a species may extend their lives because of one unexpected invention: contraception. The latter increased the average age at which people have their first child and hence future generations may be unknowingly selected for longer lifespans. Future people may also have bigger brains because more and more women give birth by C-sections and babies with larger heads which would have previously died are very likely to survive now.
You could say that all medicine is anti-aging medicine because the purpose of medicine is extending human lifespan and healthspan or at least maintaining some dignity if nothing can be done anymore. Since the phenotype of aging is influenced not only by genes but also by the environment, you may also say that public health measures and any medical treatment postpone aging or modify its phenotype to some degree. If you received the polio vaccine as a kid, your aging self will be different than if you haven’t and you contracted the disease.
The anti-aging industry already exists. It just doesn’t bear this name. It’s simply called medicine.
References
Peer-reviewed papers
Coelho, M., Dereli, A., Haese, A., Kühn, S., Malinovska, L., DeSantis, M. E., … & Tolić-Nørrelykke, I. M. (2013). Fission yeast does not age under favorable conditions, but does so after stress. Current Biology, 23(19), 1844-1852.
Mueller, L. D., Shahrestani, P., Rauser, C. L., & Rose, M. R. (2016). The death spiral: predicting death in Drosophila cohorts. Biogerontology, 17(5-6), 805-816.
Nagai, J., Lin, C. Y., & Sabour, M. P. (1995). Lines of mice selected for reproductive longevity. Growth, development, and aging: GDA, 59(3), 79-91.
Popular science articles
Rose, M. R. (2011). Ageing: life begins at 90. New Scientist, 211(2824), 42-45.
Books
Mueller, L. D., Rauser, C. L., & Rose, M. R. (2011). Does aging stop?. OUP USA.
Rose, M. R. (2005). The Long Tomorrow. How Evolutionary Biology can help us Postpone Aging. Oxford University Press, New York.
Robertson, R. M., & Margarida, M. (Eds.). (2004). Methuselah flies: a case study in the evolution of aging. World Scientific.
De Grey, A., & Rae, M. (2007). Ending aging: The rejuvenation breakthroughs that could reverse human aging in our lifetime. St. Martin’s Press.
Anca Ioviţă is the author of Eat Less Live Longer: Your Practical Guide to Calorie Restriction with Optimal Nutrition ,The Aging Gap Between Species and What Is Your Legacy? 101Ways on Getting Started to Create and Build One available on Amazon and several other places. If you enjoyed this article, don’t forget to sign up to receive updates on longevity news and novel book projects!
Don’t miss out on the Pinterest board on calorie restriction with optimal nutrition where she pins new recipes every day.
https://www.pinterest.com/longevityletter/eat-less-live-longer/
Or the Comparative Gerontology Facebook Group where you can join the discussions on how species age at different speeds and what could be the mechanisms underlining these differences!
https://www.facebook.com/groups/683953735071847/
“But I never bought into the idea that you could solve a problem without understanding it first, especially a problem as complex as aging. ”
— that’s true if you want to fully solve it. But if I recall correctly, SENS people are fond of the idea of buying yourself time: discover an approach that rejuvenates or postpones aging just enough so that we can live till another research breakthrough is made.
To this end, it’s enough to understand just a small part of the problem of aging, in order to make SOME progress. And sometimes, all is needed is a good educated guess, that is tested and found to indeed work.
(One example in cancer research: the p53 genes were found to be large number in elephants (20ish); a lab found a way to duplicate that gene in mice, and, lo and behold, the mice had less cancer while still living as long as other mice!)
Some problems are just too complicated to fully understand them before it’s too late to matter…
Of course, I’m not qualified to defend the details of SENS (I read the summary and it made sense on a naive interpretation like mine). But I like that it promotes a goal-oriented approach, to focus the efforts of larger groups of researchers. If other people know better, let them suggests better programs, by all means.
SENS is better than nothing but I know how hard it is to justify basic research with no aim in view. Yet basic research leads to most efficient solutions to complicated problems. This doesn’t exclude buying time with SENS and also with any available technology like access to clean water and vaccines.
” It didn’t occur to me that you could bring evolution in the lab, play with parameters and create longer-lived model organisms which you could then compare with their normal variants.”
— I like this idea, as one keeps all variables same (controlled) except for longevity (target). I’m wondering why don’t more researchers pursue it??
As this is only feasible for shorter lived species, it should be complemented with observational studies.
Within a species, there’s one company sequencing genomes of people for that goal: https://en.wikipedia.org/wiki/Craig_Venter#Human_Longevity,_Inc.
(I wish there were more public research of this kind)
Between species, it will be useful to find and research 2 or more species that differ significantly in lifespan, while having many other parameters similar: similar living environment, evolutionary closeness to one another, and, preferably, close to humans as well.
(I mentioned this in my comment here https://longevityletter.com/the-3-things-lifespan-record-breaking-species-do-right/ )
“Dr. Michael Rose’s hypothesis is that this may be due to the invention of agriculture which postponed the last age at which humans reproduced by increasing fertility through abundant calories. The latter also led to an increased population size so it became easier to find mates later in life. According to this hypothesis, returning to a hunter-gatherer lifestyle, particularly after midlife, may make it more likely to reach the late life stage.”
— I did not understand why you concluded that. The hypothesis was agriculture, not hunter-gathering… or what?
Sweet potatoes- thanks for reminding about them! (and they are good tasting too 🙂 )
“The anti-aging industry already exists. It just doesn’t bear this name. It’s simply called medicine.”
— I totally agree with your conclusion. ( In fact, I was trying to (somewhat unsuccesfully) convince an old friend of mine about such things… conversation might still continue https://passingeons.com/review/the-stoic-challenge/ , comments section)
My only complaint with that is that medicinal research, as a field, doesn’t make explicit and concerted efforts to eradicate aging. It seems to me that progress so far has only been made by attacking symptoms of aging, as opposed to root causes.
Thank you for your thoughtful comment!
Evolutionary aging research costs a lot more money and prestige than simplistic research where molecule A targets B so it has an effect C on disease X. I guess this is why more researchers don’t pursue this avenue.
Regarding the 2 species to be compared, I replied you there in the other blog post.
To keep it short, agriculture is the opposite of a hunter-gatherer lifestyle so if according to this hypothesis, agriculture is the problem, I deducted that a hunter-gatherer lifestyle is the solution. It is easier to adapt to a novel lifestyle when you’re young than when you’re crossing midlife so if generation after generation, humans are adapted to a hunter-gatherer lifestyle and not to an agricultural one, it is important to revert to this after midlife when adaptation to the novel foods of agriculture doesn’t work as well as when one is young. But this is just a hypothesis – I don’t follow the Paleo lifestyle because I haven’t seen any centenarian in clinical practice avoiding cereals and milk products. It’s also not practiced in any centenarian hotspot around the world. Instead, what I encountered in clinical practice but also by studying such hotspots is a diet low in calories, high in nutrients (mostly from veggies and seafood) and lots of exercise (not in gyms, but in agriculture, go figure!). I’ve also noticed beekeepers are particularly long-lived (again a combination of hard work and lots of nutrients from the beehive).
My confusion is that you think/thought agriculture is the problem in the evolution.
“-a later last age of reproduction will prolong the aging phase and will postpone the transition from aging to late life” : but this also directly implies that healthspan will increase (as reproduction requires a certain health), and so I actually concluded that agriculture increased average lifespan for humans.
Yes, I understand that “-an earlier last age of reproduction will compress the aging phase” , but it can happen that although aging phase is compressed: during it, the mortality accelerates faster than when have a longer aging phase, so that mortality reaches similar value by the end of the phase.
Then you reach the late life earlier, but with similarly and so high mortality rate, that it may not matter at all– in fact , could be shorter lifespan than when later last age of reproduction and later arrival of late life.
In humans, we have a last reproduction age of around 50 (women) (say b/c of agriculture) but there’s another 50 years (+/-5) of aging before the late phase, during which most of the mortality rate increase happens. Then in late life, people live what, 10 years on average? If you make last reproduction age at say 30, you could still have those 50 years (or more) of aging before getting to late life, and when you get there you could be just as frail and overall not live longer.
In fruit flies, did you read that the flies with earlier last reproduction age, actually got a bigger lifespan ?
Three things I want to add to your comments:
1. What is healthy for an individual is not necessarily healthy for the species. Prolonged fertility is good for the individual since with the loss of it comes a higher risk of cancer and cardiovascular disease but prolonged fertility span generation after generation will prolong the aging phase of life.
2. ” reproduction requires a certain health” – more so in women than in men even if the effects of both genders matter regarding the average lifespan of a sexually-reproducing species like humans.
3. ” during it, the mortality accelerates faster than when have a longer aging phase, so that mortality reaches similar value by the end of the phase” – exponential growth is much faster than linear one so mortality will still increase faster during aging than after the aging phase.
At your point 3. : I guess I didn’t explain myself clearly: yes, I meant that during the aging phase not after it.
And “exponential growth is much faster than linear one” — oh, you think I wouldn’t know that? (I guess you forgot my backgrounds , lol)
Sorry for the misunderstanding and no, I didn’t forget your background 🙂
So you mean that if the aging phase is compressed that also means a model of accelerated senescence compared to normal, right?
And if you forgot, I can’t blame you, as I don’t remember myself what I told you about my background ( physics, math, some biology and neuroscience, and computer science more recently)
Yeah, I meant a model with compressed aging phase could, in principle, have a stronger acceleration of senescence during it compared to a model with stretched-out aging phase. So that by the end of the aging phase, mortality rate of the 2 models can be of similar order.
(Exponential growth can be with different rates/coefficients of growth – as you know- )
And one more thing: even if it’s true that agriculture led to later last age of reproduction compared to hunter-gathering, and even if it’s true that that led to longer lifespans, you cannot conclude from that that it would beneficial for you personally to practice hunter-gathering… (obviously it won’t make you personally have an earlier last reproduction age).
Though surely may be other reasons to suspect hunter-gathering has health benefits (less cheap sugars and more varied diet, more exercise…).
By the way, if you google-search for “Late-life mortality deceleration” you will see that most (or at least most popular) latest results (2011-2019) contradict this phenomenon in humans, ascribing it to statistical and human errors.
Which casts big doubts on the extrapolation Dr Rose wants to make from fruit flies to humans.