Significant Single Gene Longevity Mutations in Humans: What Are the Odds?
Prior to the discovery of single genes that could be mutated, silenced, or otherwise altered to significantly extend longevity in lower animals, such a thing was thought very unlikely. Which is to say that nobody really thought about it at all - it wasn't a possibility within the paradigm of understanding for aging and metabolic processes. Now, of course, researchers have a variety of longevity mutations in hand in species ranging from worms to rodents, and more are being discovered with each passing year. Some technology demonstrations built atop these mutations have extended healthy life by as much as 50% in mammals (by combining a few methods), and far more than that in nematode worms.
But I'm not an advocate of chasing metabolic manipulation as a primary method of enhancing human longevity. This is primarily because it will produce therapies that only slow aging, and are thus far less effective than a repair strategy aimed at reversing aging. Slowing aging does little for those already old, and is a one-shot deal. Repair methodologies help the old and can be used over and again. Beyond that one can also reasonably argue that the repair strategies will be less costly to develop given the present state of scientific knowledge.
One has to regularly re-examine one's prejudices, however. The question for today is whether there exist as yet undiscovered and comparatively simple mutations in humans that will significantly extend healthy and maximum life spans. How likely is this, given what we know to date? Are potential human longevity mutations worth chasing?
The layperson only has a couple of data points to go on here:
- No human study can yet point to genetic differences that add up to more than a couple of years of life expectancy, and that's usually a matter of statistical analysis and/or resistance to one specific age-related disease.
- Single gene longevity mutations in other species were not thought plausible until discovered.
- Based on results obtained in calorie restriction studies, researchers don't expect metabolic changes to produce anywhere near as great an effect on longevity in humans as they do in mice.
- Much of the work on human longevity effects is inherently speculative; researchers are still striving to develop good tools that predict life expectancy or determine age in longer-lived animals.
We humans are already an unusually long-lived species if you compare us with other mammals of similar size. That seems to bring with it a diminished return on metabolic changes with significant effects in lower animals. It's an open question as to whether that applies to changes that go beyond what the body is capable of itself in response to diet, and beyond the minor variations in human genotypes.
Based on what I've seen over the past decade, I would not be surprised to see mouse life span doubled ten years from now through some ingenious combination of simple gene engineering and altered cellular processes - i.e. through slowing aging rather than repairing damage. Researchers are already half way there. Equally, I would not be surprised to see single human genes discovered that when manipulated or silenced can produce an expected change in life expectancy on a par with the expected changes for exercise and calorie restriction. This is to say something between a few years to an additional decade of healthy life, and an unknown effect on maximum life span. (Note that I say "expected" here. Even the figures for exercise based on demographic studies could be overturned with sufficient new data, and life expectancy predictions for human calorie restriction are just that - predictions).
I would be very surprised if anything greater than that jumps out of a single gene mutation in humans. But my expected level of surprise is not a rigorous assessment. The rigorous assessment would be "probability unknown." There were all sorts of plausible evolutionary arguments as to why researchers wouldn't discover any simple change in an animal's genes that greatly improved its longevity - all wrong, obviously. Similarly, all it takes is one discovery in humans to make the present wisdom gained from calorie restriction studies and further evolutionary arguments wrong as well. Our present longevity is very much determined by evolution - look at how widely life spans vary between similar species - but that doesn't mean we yet fully understand why and how.
So as research in lower mammals and other primates continues, scientists will increasingly build upon it to explore alterations in the human genome. But I don't see it as the best path forward to enhancing longevity for those of us reading this today. We will be decades older before any material benefit is realized - and that much less able to benefit from a technology that can only slow down aging. Our self interest is much more aligned with projects that could greatly improve health and longevity for the aged, and which could be realized in a similar time frame.
I been diagnosed with Andersen-Tawil Syndrome. It is extraordinarily rare.
There has been gene mutation somewhere but I don't know if I inherited those mutated genes or if they are original to me. My blood and skin samples are still undergoing testing.
This may or may not be pertinent to this article--I have noticed that I seem to have always aged much more slowly than my contemporaries.
This might be life style. But, if it is a part of the syndrome, I think it might be worth science taking a look.
im also being evaluated for andersen tawil syndrome..come check out the andersen tawil syndrome page on facebook!! Id also like to invite you to join the periodic paralysis association as they have a lot of information.. also in my family very little wrinkling young looking skin but trade off is not quite worth the price we pay,,, karen
I ve learnt a lot from all your articles
Question: Does the idea of using our own stem cells to rejuvenate organs through out the body
Seem to be a practical and more easily attained method of "re-booting" the entire body?
Just my thoughts!
John w Beld
Engineer & Naturalist
@karen carr Wouldn't that be why though? The price you pay is dear indeed do not doubt my veracity on this but i would question it in this way.. is not the very point of the article the concept of being able to almost like, "lift the hood", as it were, on these genes to be able to manipulate them and thus actually achieve a noteable difference.. so looking into the blueprints of this Andersen Tawil syndrome... would not the point BE to be able to find out not only what keeps YOUR skin so lovely as i'm certain it is (don't worry i'm 30 and just jealous :P)but as well how it ties in when the rest of it is doing what it's doing to you.. and better yet is there a way to turn the damage off but yet keep the rejuvenation active without any longterm deficits to speak of no doubt? Thus we could "prepay" that cost in some way... less terminal? shall we say?
Have you heard about human accelerated regions of the human genome? HARs are the areas that have changed at the highest velocity between humans and other primates. Wikipedia says there are 47 HAR genes. Putting all 47 of these HAR genes in one mouse at $2k per gene is about $100k, and then making 8 clones is about another 16K. 8 clonal mice is sufficient to calculate a p value at .05 So it looks like there is an experiment that could be done for near $120k that could see if mice live three times longer. The numbers are approximate but if they are order of magnitutude plausible then it is less than 1.2 million $.
Ironically, having shorter generations helps speed up the genetic changes, so the most rapidly mutations genes are not very likely to promote longevity.
As for trying human genes in a mouse... For sure we will find some interesting insights but probably nothing directly related to longevity. After all we do different from the mice. They can reach sexual maturity in less than a month (21d). With such a short generation time they don't need to maintain long lived organs and tissues the same way as see do. In fact, I can imagine a mouse with slot no dividing cells ( need then for the skin, stomach, procreation, and a few others finding) which good frickin just fine. At least in a laboratory setting...
In one of the later remarks in your post, you said: "Our present longevity is very much determined by evolution - look at how widely life spans vary between similar species". From my perspective, evolution does not constitute a mechanism at the level of the individual in that sense. Life span is a mechanism created and controlled by genetics and epigenetics in each individual. These mechanisms can be seen as death programs. If the large variation in the life span of similar species is the result of transgenerationally passed epigenetic clock differences we will not find hard mutations demarcating them. However, they will still be programmatic death mechanisms that could homeostatically resist attempts to use SENS methodologies to ameliorate senescence effects.
For this reason, I think that it is also worthwhile to proceed on the front of developing a better understanding of aging as part of the general evolution theory. Josh Mitteldorf deals with this topic well in his book "Cracking the Aging Code" but reaches a group-selectionist conclusion in the end that I do not subscribe to.
Aging: taking responsibility
As a long time immigrant, I love re Americans take charge attitude. I have no statements to make against funding research. But I do fault my heroes for not thinking as in the following. All ant-aging efforts are two categories - non-doctor and doctor responsibility. The first category are 3 methods where doctors do not enter, but to perform requested operations. Second is wait for things to become actionable, tracking the research and funding. 3 actionable methods are soft methods, BNBE (beneficial neutral blood exchange) and thymus methods. The Second group is all derived from Yamanaka factors. All thinking smart consumers will use some Horvath techniques to create data points for the future and write up procedure tried. Soft methods are all believed in from advice, Pterostilbene and NMN.
We should approach improving healthspan and lifespan incrementally wherever possible. Theoretically, substantial improvements in population longevity over time by using preimplantation genetic screening to reduce the risk of diabetes, heart disease, etc with each generation.