Back in a July 2009 blog post Life extension by a factor of 10, I described how radical life extension has been achieved in baker’s yeast. The most-recent blog entry posted two days ago New extraordinary longevity lessons from the nematode chronicles how researchers over 20 years have managed to discover interventions that multiply the lifespans of nematode worms (C-elegans) by a factor of seven. This raises the question explored in the present blog entry: Why have researchers over the same 20 years essentially gotten nowhere in significantly extending human lifespan? This blog post examines what has held us back and also sounds a note of optimism based on what is happening. My opinions about what we would have to do to move forward more concertedly will be treated in yet-another blog entry. I start out on a positive note.
Why nematodes are a wonderful model organism for study of aging
Virtually everything related to genetic pathways affecting longevity in mammals and humans was discovered first in primitive organisms like baker’s yeast and the nematode. I am talking about the major pathways known to have a potential for human life extension including mTOR, SIRT1 and FOXO/DAF16. Nematodes are ideal organism for first-pass studies of longevity because, put simply, you can freely mess with them. In more detail:
· As I pointed out in the blog post MicroRNAs in cancers and aging, and back-to-the-nematode “Nematodes are “– simple enough to be studied in great detail. Strains are cheap to breed and can be frozen. When subsequently thawed they remain viable, allowing long-term storage.”
· A whole supplier industry has grown up for C-elegans. You can buy C-elegans DNA here, and if you want the worms themselves you can buy them from the C-elegans Genetics Center for $7 per strain if you are in a university or not-for profit lab; otherwise cost is $100.
· “C. elegans is transparent, facilitating the study of cellular differentiation and other developmental processes in the intact organism.”
· Nematodes are cheap to maintain, feed and breed. Unlike people, they don’t need fancy housing, education equal opportunity or health care and they don’t vote. And they don’t vocalize religious or ethical scruples about what is done to them. They don’t yell or cry.
· Nematodes don’t hire lawyers so you can do things to them you can’t do to humans, like modify them genetically. If you are a nematode researcher, you don’t need to worry about consent forms, the FDA or the Animal Rescue League.
· Nematode longevity research is roaring ahead in a worldwide community of thousands of nematode researchers. See the Caenorhabditis elegans WWW Server for WormBase, C-elegans meetings, jobs, software, recent papers, worm genomes, Wormatlas, Wormbook, C elegans movies and much more. Life-extension progress reported in the previous blog entries is just a start. “There’s careers, money and fame in them there worms.”
· The little critters have very short normal lifespans (around 20 days), so in a couple of weeks interventions affecting lifespans can be studied. In a couple of months it is possible to perform longevity and generational experiments that would take centuries in humans.
· The critters have evolved very effective stress-management strategies to get them through their inactive dauer stage, and most of those strategies are conserved right up through the evolutionary hierarchy and work, albeit somewhat differently, in us. As stated in the 2010 publication An overview of stress response and hypometabolic strategies in Caenorhabditis elegans: conserved and contrasting signals with the mammalian system, “Caenorhabditis elegans, undergoes a state of hypometabolism called the ‘dauer’ stage. This period of developmental arrest is characterized by a significant reduction in metabolic rate, triggered by ambient temperature increase and restricted oxygen/ nutrients. C. elegans employs a number of signal transduction cascades in order to adapt to these unfavourable conditions and survive for long times with severely reduced energy production. The suppression of cellular metabolism, providing energetic homeostasis, is critical to the survival of nematodes through the dauer period. This transition displays molecular mechanisms that are fundamental to control of hypometabolism across the animal kingdom. In general, mammalian systems are highly inelastic to environmental stresses (such as extreme temperatures and low oxygen), –“
· C-elegans provides an excellent working model for examining how a limited number of transcriptional regulators can mediate to influence downstream aging lifespan effector genes.
· “However, there is a great deal of conservation between the signal transduction pathways of nematodes and mammals. Along with conserving many of the protein targets in the stress response, many of the critical regulatory mechanisms are maintained, and often differ only in their level of expression. Hence, the C. elegans model outlines a framework of critical molecular mechanisms that may be employed in the future as therapeutic targets for addressing disease states(ref).”
The 2006 mini-review Recent aging research in Caenorhabditis elegans summarizes some of the conserved pathways studied in C-elegans. “Evidence gathered over the past 15 years shows that the nematode Caenorhabditis elegans is excellently suited as a model to study aging processes in the entire organism. Genetic approaches have been used to identify and elucidate multiple mechanisms and their corresponding genes that limit the life span of C. elegans. These highly conserved pathways include the well-studied insulin/IGF-1 receptor-like signaling pathway, which is thought to be a central determinant of life span, since several other mechanisms depend or converge on the insulin/IGF-1 pathway transcription factor DAF-16/FoxO. In this review we focus on new insights into the molecular mechanisms of aging in C. elegans, including new genes acting in the insulin/IGF-1 pathway and germline signaling. In addition, stress response pathways and mitochondrial mechanisms, dietary restriction, SIR2 deacetylase activity, TOR and TUBBY signaling, as well as telomere length contribution are discussed in relation to recent developments in C. elegans aging research.”
Why human beings are a terribly difficult model for the study of aging.
Put simply, you can’t mess with people except extremely carefully. In detail:
– Obviously, we are a lot more complicated than nematodes and what works to keep them young might not work for us and, in fact, could harm us.
– Since human life is regarded to be sacred, you can’t ethically, morally or legally do things to people like knock out or add to their genes. The consequences for a researcher doing such things could be being thrown out of his university, driven out of his profession, ending up in jail, or facing billion- dollar lawsuits.
– People yell, cry, complain, see lawyers or can get guns and shoot you.
– It is extremely expensive to research anything involving large numbers of humans. Big pharma companies spend hundreds of millions of dollars on very specific clinical trials. They won’t spend that kind of money on longevity treatments unless they can see multi-billion dollars payoffs in a few years.
– Carefully-designed longevity clinical trials, if there were such things, would take centuries. And it makes no sense to conduct such a clinical trial because in 5-10 years research progress will make the original interventions being examined in such a trial obsolete.
– Besides, you can’t conduct a government-recognized clinical trial on a “cure” for aging in people because aging is not regarded by the government to be a disease and is not recognized as an indication for clinical trials.
– A small university laboratory with a modest budget and hard-working research associates can study and produce significant research results about nematodes; it takes a big pharma company spending hundreds of million dollars to conduct a single clinical trial with very limited objectives on people.
– There is no big money in human longevity research. The NIH spends a pittance on aging research compared to what it spends on cancer or HIV research, and pharma companies generally won’t touch it.
– The social context in the US at least is strongly against human genetic modification. And, I opine that vociferous fundamentalist religious groups will probably be against radical life extension by any means. The people who are pro-life for fetuses may well turn out to be anti-life when it comes to older people and take the viewpoint “We should not mess with God’s plan for people growing older and passing away when their time comes.” And as a consequence “We should not spend a single penny of government money on life extension.” They forget that God’s original plan for humans was to have most of us pass away by age 25. The blog entry Getting the world ready for radical life extension examines what would probably go sour if someone went public with an effective “cure” for aging tomorrow morning.
– Above all, what is missing is a general framework of thought and shared values that says radical human life extension would be a very good thing and something that should be pursued systematically with significant resources. Such a perception may exist in the minds of a few visionaries, selected researchers and readers of this blog. But it does not exist out there in the general public or even in the programs of the agencies that fund aging research. Instead, the general image evoked by extending life span is more doddering unproductive retirees kept alive by expensive drugs fed through tubes and filling up nursing homes and hospitals, creating terrible auto accidents, driving social security broke ever-more quickly, and running health care costs even more over the top. Most people don’t get the essential point that increasing lifespan and increasing healthspan are the same thing and that the biggest risk factor for the costly diseases of aging like Alzheimer’s, Parkinson’s and most cancer is aging itself. The point is obvious when you think about it, but most people don’t think about it.
I will say more about these last points in a next blog entry after this one Preparing for the war on aging. But first I want to review what might happen with life extension if we keep going as we have been going.
Is there hope for radical life extension in humans?
The bottom line is that if radical life extension in human’s is to take place in humans the way things are going, it will be something that we blunder into rather than be the result of a specific R&D program. There are reasons, however, for hope that we may well blunder at least part of the way:
– Nematode research provides a good start for going on to higher animals The research on nematodes has told us a lot about the operation of genes and pathways that are largely conserved in mammals and humans, and provides well-defined guidelines for research that leads to radical extension of lifespans in mice as the next step. We know there is remarkable similarity among “longevity” genes and related pathways across a wide spectrum of species ranging from yeast to worms to flies to humans. See the blog entry Longevity Genes and two Fantasies. As far as mice goes there appears to be several interventions that increase their lifespans by around 30% and “A few transgenic species of mice have been created that have maximum life spans greater than that of wild-type or laboratory mice. The Ames and Snell mice, which have mutations in pituitary transcription factors and hence are deficient in Gh, LH, TSH, and secondarily IGF1, have extensions in maximal lifespan of up to 65%(ref)” The next step is to double up like what was done with nematodes and then find out how to quadruple mouse lifespans. We are much more like mice than like nematodes. But mice don’t complain or sue much more than nematodes do.
– Medical and drug research for diseases of old age will probably yield anti-aging therapies. A lot of money is being spent on cancer research, Alzheimer’s Disease research, diabetes research, and research on other diseases of old age. Not curiously, potential therapies that can slow down or stop such diseases are also potential anti-aging interventions. For example, inhibition of the mTOR pathway via rapamycin both wards off cancers and Alzheimer’s disease in mice and extends their lives. See the 2010 publications Rapamycin extends maximal lifespan in cancer-prone mice and Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. According to an April 2010 article in Gen, “This marks the second report linking rapamycin to AD treatment within the last month or so. The previous study, published February 23 in The Journal of Biological Chemistry (JCB), highlighted an interrelation between mammalian target of rapamycin (mTOR) signaling and A-beta. Using a different animal model of AD, the group found that pharmacologically restoring mTOR signaling with rapamycin rescues cognitive deficits and ameliorates A-beta and tau pathology by increasing autophagy. — Additionally, in July 2009, a different group of Barshop Institute researchers and colleagues at two other institutions reported that microencapsulated rapamycin extended the life span of mice, possibly by delaying aging. — “The fact that we are seeing identical results in two vastly different mouse models of Alzheimer disease,” Dr. Galvan added, in reference to the February JCB paper, “provides robust evidence that rapamycin treatment is effective and is acting by changing a basic pathogenic process of Alzheimer that is common to both mouse models. This suggests that it may be an effective treatment for Alzheimer in humans, who also have very diverse genetic makeup and life histories.”
This last description makes me smile because the “basic pathogenic process of Alzheimer that is common to both mouse models” is probably just the complex process of aging itself. The same basic pathogenic process of aging invites age-related cancers, Parkinson’s disease, advanced Type 2 diabetes, coronary heart disease, macular degeneration, etc. – all those things that cripple and eventually kill us when we grow old.
– Certain dietary supplements may be life-extending. Despite lack of hard evidence such as provided by clinical trials, certain dietary supplements like several listed in my combined anti-aging firewalls regimen may be life extending. Regarding resveratrol, for example, see the blog entries SIRT1, mTOR, NF-kappaB and resveratrol, Visit with Leonard Guarante, and What does resveratrol do? Regarding curcumin, you could review Curcumin, cancer and longevity. And I have discussed many other dietary substances and supplements in this blog, ones which convey important health benefits and with potential probably-mild life-extending properties: (ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref)(ref).
– Social, economic, technical, business, infrastructure and knowledge factors are operating together to ever accelerate the discovery of anti-aging interventions, albeit from a very low current base. See the blog entry Factors that drive Giuliano’s Law.
– A whole DNA supplier industry has developed to facilitate longevity as well as medical research. You can find links to buy DNA for mice, guinea pigs, rats, chickens, fish, cats, rabbits, zebrafish, dogs, cows and simians here.
– The databases of basic knowledge related to genomics, epigenomics and related ‘omics” are rapidly increasing in size and sophistication as the cost of whole-genome sequencing plummets(ref).
– Personalized Predictive Preventative Participatory Medicine (PPPPM) is slowly being adopted and will in time transform the practice of medicine to where it is much more science-based and likely to open the door to more and more interventions that are designed to prevent diseases and, in the process, extend lifespans. See the blog entries Harnessing the engines of finance and commerce for life-extension, Personalized medicine – reducing the cost and improving the effectiveness of health care, and Transformed State of Medicine – 2025.
– Genome-wide association studies are telling us more and more about what creates the diseases of old age, even, cancers, and how they can be averted. See the blog entry Genome-wide association studies.
– Social evolution and epigenomic changes are driving longer lifespans. See the blog entries Average US life expectancy up 73 days in one year, Antagonistic pleiotropy revisited – for the last time, and Ever-increasing longevity– is epigenomics involved?
In summary, multiple social, economic, demographic, scientific, and technical factor are interacting to create an exponential growth in knowledge related to longevity, and, eventually, longevity treatments. The problem is that we are starting from a low base. In 40-50 years we will be improving practical longevity prospects at a furious rate. We are improving them now, but progress is relatively snail-paced.
One Scenario for the emergence of longevity drugs
One possible scenario for the development of anti-aging therapies could conceivably go like this: a drug is developed for Alzheimer’s disease – say rapamycin itself or a rapamycin analog – that also delays aging. As the word gets around that the drug delays aging and slows down the onset of other diseases like cancers, people who do not have AD or cancer will also start to demand that drug.
And there are a number of other drug candidates that could also get the longevity ball rolling. In the previous blog entry where I discussed nematode aging pathways, I discussed how PDEF is being investigated as a negative regulator of certain human cancers while its nematode counterpart ETS-4 is a known lifespan regulator. An anti-cancer treatment that is life-extending might be based on sestrin proteins. See the blog entry Sestrins, longevity and cancers. On another front yet, Sirtris pharmaceuticals is “creating revolutionary medicines for the diseases of aging.” “Our research focus is on modulating the sirtuins, a recently discovered class of enzymes involved in the aging process.” To the extent that Sirtris’ products will work, since they are based on activating the SIRT1 gene they will almost certainly be life-extending. Yet-another possibility are drugs in Phase III clinical trials that mimic the effects of variants of the CEPT gene, variants that are protective against cardiovascular diseases, memory decline and dementia and that are found in centenarians and thought to confer longevity. See the blog entry CETP gene longevity variants. And you can bet that once one longevity drug starts to reach blockbuster status, other big-pharma companies will start pouring billions into longevity drug R&D.
In short, there are a number of drugs being researched or developed for diseases of old age that could also confer important longevity benefits. And that is how the first longevity-enhancing drug could get on the marketplace
The prospect for breakthrough human longevity
We are likely to see only slow incremental shifts in our longevity, even though the pace of research and knowledge is picking up. I do not expect anything like the factor of 7 increase in lifespan over 20 years as was the result of research on nematodes. Perhaps, if we are very lucky, we will see a 15% increase in expected human lifespan for people who follow certain interventions within ten years. This is because our society is simply not prepared now to invest significant resources in really prolonging life – say doubling lifespans. And, if researchers seriously tried to do that they would probably be fiercely resisted and burned at the academic, moral and legal stake. See the blog entry Getting the world ready for radical life extension. “The idea of people living hundreds of years has about as much credibility today as the idea of the world not being at the center of the universe had in 1540. Intellectually and in terms of our laws, institutions and actions, we are just not ready for radical life extension.” I illustrate this point with a story of what could well happen if a good life-extension drug were developed right now. And I concluded “Above all, there is a need for a major shift in general perspective regarding life extension FROM more and more doddering, sick, non-functional, non-contributing individuals drawing social security, filling nursing homes, driving their grown children crazy, having automobile accidents and driving health care costs ever-higher, TO more and more healthy, creative, fully-functional working individuals in their 70s, 80s, 90s and beyond who are not getting the diseases of old age, and who are more than doing their part to contribute to our society in every way.”
Until that shift in perception changes, we may continue to get nowhere towards the goal of real breakthrough longevity. Being a visionary though, in a subsequent blog entry I will outline how I think a big breakthrough possibly could be achieved within the next five years. Stay tuned!