Slowing the aging process or reversing it?
Most people would presume that slowing the aging process might be a great deal easier than reversing it. I tend to agree that at first glance this would seem to be a perfectly logical assumption and, indeed, in all probability the first therapies are likely to be interventions which slow the aging process and increase an individual’s health span. Current indications are that at least 7 or 8 extra years of healthy life are within striking distance and research involving Senolytic drugs, NMD and NAD+ look very positive see this link. Delaying age related decline is a number one priority in the war on aging especially because North America, Japan and the EU all have major issues with a rapidly aging population.
Whilst adding 7 or 8 healthy years is obviously extremely worthwhile, it is important that we do not go down the potential dead end of seeking to simply slow aging at the expense of developing robust rejuvenation therapies. There is a good reason for this. The first one, as I pointed out in the last section, is that rejuvenation therapies will not require a complete understanding of every process involved in aging and metabolism, this is because we will seek only to repair the damage that accumulates as we get older and, fortunately, we do have a good understanding in how young bodies function and the goal would be to restore the body to a biological age that is younger than its chronological age. These rejuvenation therapies will be much more effective than simply trying to slow aging by tacking on a few extra years which simply delays the inevitable.
I am often asked why we will develop anti aging interventions first which just slow the aging process if this needs a detailed understanding of metabolism which is an area in which we are not very knowledgeable, the answer to this is that I think we know enough to get one or two shots at this route as an interim measure and the proof came in July 2009 with tests concerning a drug called Rapamycin also known as Sirolimus. In ground breaking experiments the drug gave elderly mice the human equivalent of 13 extra years of life. I do not think we will get the 13 years from which was seen in the mice but a significant gain of 10 to 15 years is possible if we succesfully combine therapies involving various recent breakthroughs such as removal of senescent cells and stem cell treatments . The research in Rapamycin indicates that the life extension did not come from just postponing a few specific diseases, Jackson Laboratory gerontologist David Harrison who was a leader of one of three research teams which conducted the experiments separately said “the treatment didn’t start until the mice were 20 months old the equivalent of a 60-year-old human. No other intervention has been so effective starting late in life.”
The stumbling block with Rapamycin is that it is an immunosupressive which means we could not benefit from it in its present form although current research looks likely to lead to derivatives of this compound which do not display the negative side effects and the one showing the most promise currently is everolimus. The important factor in the original Rapamycin study is that the results were replicated independently in three different laboratories. Mice were already old when they started treatment. They were also genetically unconnected, this meant that the mice could be expected to die in numerous different ways. This point is vital for any potential anti-aging drug to have an effect that could offer potential to be translated into a usable compound for humans. In the study, over 1,900 mice whose genetic variation was roughly comparable to that found in humans, were fed Rapamycin, treatment starting when they were around 20 months old, this is comparable to around 60 in humans. The average date at which 90 percent of the mice were dead rose from 1,078 days to 1,179 days in males and from 1,094 days to 1,245 days in females. In proportional terms, old age lasted one quarter longer than expected for males and two fifths longer for females. Initially, the experiment was not supposed to have started so late but a number of factors caused delay and this proved to be extremely beneficial because, when experiments using Rapamycin were carried out on 9 month old mice, they had little effect. Harrison said “it is possible that for some agents the most beneficial effect will only start late in life.”
What we do not really understand is how Rapamycin operates. We know that its target is a gene called mTOR which stands for mammalian target of Rapamycin - this gene produces an enzyme which in turn initiates a cascade of cellular signals which play a role in the regulating of cell growth, mitochondrial function and breakdown. What I find especially interesting is that a significant amount of evidence indicates that mTOR’s pathway shares a large number of genes and associated functions with the sirtuin pathway SIRT1 which is targeted by Resveratrol and NMD although the jury is still out regarding the issue of whether Sirtuins have a role in anti aging research.
The current breakthroughs in the area of telomere research relating to the lengthening of telomeres is of consideable interest because the research is moving rapidly and clearly it is technically possible and highly probable it will translate into humans. The primary concern with the lengthening of telomeres used to lie in the theoretically elevated risk of cancer but this problem does not apply based on the current research which you can see on the Stanford University website at this URL - Telomere extension turns back aging clock in cultured human cells, study finds - as a researcher in aging I consider this research and some supporting and complimentary research which has taken place at Harvard coupled with a additional research relating to a compounds that is related to Rapamycin tends to indicate that we are finally making significant progress in addressing the diseases of aging. Interestingly shortening of telomeres was until recently perceived by many as being a result of aging and not causal but the research at Stanford clearly repudiates this and suggests that Dr Bill Andrews was correct all along.
As far as the mechanism of delivery which has been developed so far the scientists at Stamford used modified messenger RNA to extend the telomeres so the whole process if it translates effectively into humans - and the evidence is suggesting it will - would be pretty straightforward especially when you consider the degree of extension which is 1000 nucleotides and the fact that the telomerase which lengthens the telomeres is only active in the body for 48 hours which means there is no significant risk of cancer due to the limited time during which proliferation of the cells could take place.
Will this translate into humans?
Current research proves that the aging process in a mammal is not set in stone. This means that various compounds can and will be developed which will extend lifespan. Clearly, treatments to slow aging offer a means to buy time for healthy individuals under the age of say 65 in the short term. They are, in effect, a lifeboat but they are also essentially a dead end and should be seen only as an interim step. If, however, we can develop them relatively quickly they are definitely worth pursuing and I believe we are within 5 years of a clinical trial in humans.
The reason that robust rejuvenation therapies offer a much better long term outcome than compounds, which simply slow the rate of aging, is because the treatments can be repeated again and again. The other advantage achieved by repairing the damage laid down as a result of aging means we do not need to understand all the processes of aging itself, only that we need to know enough initially to extend healthy lifespan by let us say 25 to 30 years. Rejuvenative medicine would take advantage of the rapid progress in medicine because, by the time 15 to 20 years has gone by, anti aging medicine will have moved along significantly and, whilst the first treatment bought you an extra 20 or 30 years by repairing a fair amount of the damage accumulated over 60 years of living, it did not repair it all.
15 to 20 years later progress will mean that the latest treatments will not only repair some of of the damage not corrected by the first intervention but also most of the damage that has accumulated over the 15-20 years since. Rejuvenative treatments will help the aged, who will not really be helped much at all by a therapy that merely slows the aging process still leaving them in need of constant ongoing treatments for heart disease, diabetes, elevated cholesterol, hypertension and any number of other age related conditions. The other issue with just slowing the aging process is that it does not ease the unsustainable (and rapidly growing) burden on Government sponsored medical services. All it does, in effect, is shift the problem to a date somewhere in the future which is pointless.
Something which is very clear from where we are now is that increases in life expectancy will be incremental and there is not going to be a sudden breakthrough resulting in a magic pill which you take twice daily and live forever. The rejuvenative medicine approach is a case of taking advantage of improvements in technology as they occur and not to attempt to cure aging in its entirety and it is in this area that people often fail to grasp what people like Dr Aubrey de Grey, Ray Kurzweil, Terry Grossman and many others including myself are seeking to achieve.
What type of damage and problems need to be treated?
The seven deadly things that rob a person of their youth and undermine them at a cellular level, eventually leading to death by old age, are explained below. These are the seven items identified by Dr Aubrey de Grey which must be addressed with the date which they were discovered:
1. 1955 - Cell death and atrophy: Treatable with exercise, stem cells and chemicals which can stimulate cell division. This area is also showing great promise with rapid developments in stem cell therapies.
2. 1959 & 1982 - Cancerous cells: Theoretically treatable with a type of gene therapy being developed called Whole Body Interdiction of Lengthening of Telomeres (WILT). This, however, is the item in my opinion which poses the greatest difficulties. An alternative path to WILT might also be developed within the next two or three decades due to the rapid advances in nanotechnology.
3. 1972 - Mutant mitochondria: Mutated DNA in the mitochondria causes a number of diseases. These can be prevented by moving the mitochondrial DNA into the cell nucleus where the rest of the DNA resides.
4. 1965 - Cell senescence (unwanted cells): Fat cells and other unwanted cruft can be removed surgically or by stimulating the immune system to attack unwanted cells.
5. 1958 & 1981 - Extracellular crosslinks (loss of elasticity): Certain proteins, such as those in cells making up the arteries, become too rigid over time because they bond to each other. These bonds can be broken with certain chemicals (some are already in clinical trials). Developing interventions to break these crosslinks is an area which looks very promising within the near future.
6. 1907 - Extracellular junk: “Plaque”, which collects between cells, can be eliminated by stimulating the immune system and/or by using peptides called “beta-breakers.”
7. 1959 - Intracellular junk: Molecular garbage can be prevented from overwhelming certain cells by introducing enzymes which are known to be effective against such molecules.
As Aubrey points out, we have discovered the seven biochemical processes which are the root causes of the damage which accumulates from aging. The first was discovered in 1907 but the other 6 were all discovered in a 26 years period between 1955 and 1981. If we bear in mind that a greater amount of time has now passed since the discovery of the last of the seven than it took to discover all but one of the items on the list, then factor in the massive increase in our knowledge of biology that has taken place over that time and it seems quite likely that these seven causes are all there are - crack those and it is highly likely we will have found the means to extend life almost indefinitely.
What if Aubrey de Grey is wrong?
Personally, I am confident that Aubrey de Grey is very much on the right track and one piece of strong supporting evidence is here in relation to senescent cells which is raised in point 4 above. The other compelling piece of proof to support Aubrey’s theory, as I outlined earlier, is that our risk of dying doubles every 8 years, there is some argument as to whether this period is 7, 8 or 9 years but let's use 8 as a middle figure. This means, your risk of death from disease at 22 is double what it was at 14 and, at 29, double what it was at 22. Although this doubling every 8 years does not become a major problem until you reach say 40, because it starts off at such a low level, the growth is exponential meaning it accelerates rapidly with age.
What is abundantly clear is that the only likely cause for this increasing risk of mortality is the accumulation of junk in the body and the genetic damage to our DNA which builds up over time. Aubrey's theory is that if we intervened and removed some of the damage we would make a person biologically younger and this certainly makes sense.
If it were to turn out that the Aubrey de Grey theory was wrong or that we had overlooked something vital, then great promise is still beckoning via breakthroughs in biotechnology and nanotechnology. I am confident that the biotec revolution will yield significant increases in lifespan regardless of whether Aubrey de Grey is correct or not although I am tending to view his SENStheories as offering the most likely path to radical life extension from where we stand now. As regards biotechnology, for anyone who is not clear exactly what this is, biotechnology in essence covers stem cell therapies, genetic engineering as well as a variety of cell and tissue culture technologies. These innovations should buy us 20 to 25 years of extra life within the next 15 to 20 years.
We are already in the biotechnology revolution and breakthroughs confirm that we are pretty much on target. The Holy Grail is nanotechnology, which has huge promise, is also picking up significant momentum although it lags 10 to 15 years behind biotechnology. To define nanotechnology, it is the study of the controlling of matter on an atomic and molecular scale. Generally, nanotechnology deals with structures of the size 100 nanometers or smaller in at least one dimension. So you might ask what does this have to do with aging? The answer to this is that problems such as aging and disease have the potential to be overturned. Disease and ill health, just like aging, are caused mainly by damage at the cellular and molecular level. Today's surgical tools when compared to nanotechnology are primitive, large and crude. Medical nanobots could start to appear in the 2020’s and offer immense promise when it comes to life extension.
The key here is that we have the means to attack aging on multiple fronts and it might be that we win the war on aging by combining developments from a variety of different areas of technology. What it comes down to is that we must wage the war on multiple fronts to achieve victory in the shortest possible time span.
To wrap up this page I would like to quote Ray Kurzweil.
"One scientist designed a robotic red blood cell it’s thousand times more powerful than the biological version so, if you were to replace a portion of your biological red blood cells with this respirocytes the robotic versions. You could do an Olympic sprint for 15 minutes without taking a breath or sit at the bottom of your pool for 4 hours. If I were to say someday you’ll have millions or even billions of these nanobots, nano-robots , blood cell size devices going through your body and keeping you healthy from inside, I might think well, that sounds awfully futuristic. I’d point out this already in 50 experiments in animals of doing exactly that with the first generation of nano engineered blood cell size devices.
One scientist cured type 1 diabetes in rats with the blood cell size device. Seven nanometer pores lets insulin out in the controlled fashion. At MIT there’s a blood cell size device that can detect and destroy cancer cells in the bloodstream. These are early experiments but keep in mind that, because of the exponential progression of this technology, these technologies will be a billion times more powerful in 20 years and you get some idea what will be feasible."