The Quest for Indefinite Life II:
The Seven Deadly Things and Why There Are Only Seven

Aubrey de Grey
Issue XXIV - July 30, 2004
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SENS is a practical, foreseeable approach to curing aging because all the types of metabolic side-effect whose accumulation is (or is even hypothesised to be) eventually pathogenic are amenable to repair (or in some cases obviation, i.e. disruption of the mechanism by which they become pathogenic) by techniques that, according to the experimentalists who have performed the key work on which those techniques build, can (with adequate funding) probably be implemented in mice within a decade or so. There are seven major categories of such damage, listed below, along with the leading technique or techniques that can address them.

Note: The dates given are when the category of damage in question was first proposed, in the gerontology literature, to be responsible for aging or some major age-related cause of death or debilitation. The earlier ones may not in fact be the first such mention, but they are well-known and often cited as pioneering publications in the area in question. The full citations are below the table. The relevance of these dates is that they are all over 20 years ago. The fact that we have not discovered another major category of even potentially pathogenic damage accumulating with age in two decades, despite so tremendous an improvement in our analytical techniques over that period, strongly suggests that no more are to be found -- at least, none that would kill us in a presently normal lifetime.

Damage rising
with age 

and date first identified

Reversible or obviatable by
[see links for more info]

Cell loss, cell atrophy
Stem cells, growth factors, exercise
Nuclear [epi]mutations
(only cancer matters)
WILT (Whole-body Interdiction
of Lengthening of Telomeres)
Mutant mitochondria
Allotopic expression of 13 proteins
Cell senescence
Ablation of unwanted cells
Extracellular crosslinks
AGE-breaking molecules/enzymes
Extracellular junk
Phagocytosis; beta-breakers
Intracellular junk
Transgenic microbial hydrolases

The above table is to some extent similar to Table 4.3 in Holliday's 1995 book Understanding Ageing, though with important differences resulting from the focus on types of damage rather than types of maintenance. Some of the studies cited here were in fact incorrect in their interpretation of the data they examined, but the point is that they brought the corresponding type of damage to the fore as a candidate component of aging.

Cell depletion and how to fix it

Cell depletion (cell loss without equivalent replacement) happens in some of our most important tissues -- particularly the heart and some parts of the brain. It also happens in our muscles. Sometimes the gaps where the cells were are filled up by nearby cells getting bigger (as in the heart), sometimes by replacement by other types of cell or by fibrous acellular material (this happens in the brain and the heart) and sometimes not at all -- the tissue just shrinks (this happens in muscle).

Cell depletion can be fixed in three main ways. One is by "natural" stimulation of cell division; this is how exercise increases the size of muscles, though some muscles are much harder to stimulate in this way than others. The second way is by the artificial introduction (e.g., by injection) of growth factors that stimulate cell division; this works well in muscle and may also work in the thymus, an important part of the immune system.

The third way to fix cell depletion is to introduce new whole cells, which have been engineered into a state where they will divide to fix the tissue even though cells already present within the body were not doing so. This is what stem cell therapy is. I guess I don't need to write any more about stem cell therapy: if you're reading this website, you're probably interested enough in medical progress that you know all about it already.

We need more work in all these three areas, even though they are all progressing very encouragingly.

Talks on exercise at IABG 10:
Ji      Powers      Tidball      Goto

Talks on growth factors at IABG 10:
Rosenthal      Aspinall      Brockes      Goldspink

Talks on stem cells at IABG 10:
West      Svendsen      Sefton      Haseltine

Unwanted cells and how to get rid of them

There are two main classes of cells that accumulate in the body during aging to a supernumerary degree: fat cells and senescent cells.

Fat cells tend to grow and/or proliferate to replace the muscle mass that we tend to lose with age. Interestingly, the most conspicuous fat -- under the skin, or subcutaneous -- seems to be relatively harmless in terms of increasingly our susceptibility to life-threatening diseases, unless of course it gets to the stage known as "morbidly obese" in which its sheer weight and the strain it puts on the heart are decidedly life-threatening. There is also a tendency, however, to accumulate "visceral" fat -- fat within the abdominal cavity -- and this fat seems to be really bad for us, because it promotes the progressive loss of our ability to respond to nutrients coming in from the stomach. In particular, it causes us to develop insulin resistance -- a diminished ability of insulin to signal our muscle and other cells to absorb and store sugar from the circulation -- and this eventually leads to Type II diabetes. So, we really should try to get rid of the excess visceral fat cells.

The second type of supernumerary cells, senescent cells, accumulate in quite large numbers in one tissue, the cartilage in our joints. They also accumulate elsewhere, but in much smaller numbers; however, these may still be important by being actively toxic. They aren't able to divide when they should, and they also secrete abnormally large amounts of some proteins.

Getting rid of cells is a much simpler job than most of the other things we have to do as part of SENS. In the case of fat, it's possible to use simple surgery, but that's unnecessarily invasive. There are two main other ways: we can inject something that makes the unwanted cells commit suicide but doesn't touch other cells, or we can stimulate the immune system to kill the target cells. Both approaches involve making use of distinctive molecules on the surface of the target cells: luckily, different cell types tend to have different things on their surface, so this shouldn't be too hard. But it hasn't been done yet, and not enough people are working on it -- it needs much more attention.

Talks on this topic at IABG 10:
Barzilai      Campisi

Chromosomal mutations and how to obviate them

There are two types of accumulating change that happen to our chromosomes as we age: mutations and epimutations. Mutations are changes to the DNA sequence, and epimutations are changes to the "decorations" of that DNA which control its propensity to be decoded into proteins. Luckily, we don't need to deal with these two phenomena separately, because we can obviate them both in the same way.

This is another of the areas of aging in which evolution has done the really hard work for us. We have an enormous amount of DNA, and the job of keeping it intact and functional is incredibly complicated. But evolution had to do it, so it has developed the necessary sophistication for us. We're particularly lucky in one way: evolution (since the emergence of vertebrates, anyway) has had one DNA maintenance problem that is far bigger than all the others, and that is to stop organisms from dying of cancer. Cancer can kill us even if one cell gets the wrong mutations (or epimutations), whereas any loss of function in any genes that have nothing to do with cancer are harmless unless and until they have happened to a lot of the cells in a given tissue. So, all those genes get a free ride -- they are already maintained far better than we need them to be in anything like a normal lifetime.

This means that we don't actually need to fix chromosomal mutations at all in order to stop them from killing us: all we need to do is develop a really really good cure for cancer. The one that I favour (which was the topic of SENS 3, a roundtable meeting I convened in Cambridge in 2002) is called WILT, for Whole-body Interdiction of Lengthening of Telomeres. This is a very ambitious but potentially far more comprehensive and long-term approach to combating cancer than anything currently available or in development: total elimination of the genes for telomerase and ALT (alternative lengthening of telomeres) from all of our mitotic cells. It improves on drug-mediated telomerase inhibition, because the cancer cell cannot mutate to resist this treatment -- it would have to create a whole enzyme, telomerase, out of thin air. The idea of course sounds crazy at first hearing, but it may well be possible, because the technology already exists to repopulate the stem cells of the blood and (in mice) the gut, and the skin shouldn't be too tricky either. The telomere reserve of neonatal stem cells suffices for about a decade, judging from the age of onset of dyskeratosis congenita, a disease associated with inadequate telomere maintenance. So, in theory, a decadal repopulation of all our stem cell populations with new ones whose telomeres had been restored ex vivo, but which had no telomerase or ALT genes of their own, should maintain the relevant tissues indefinitely while preventing any cancer from reaching a life-threatening stage. Cells already in the body would need either to be ablated without killing the engineered cells or to have their telomerase and ALT genes mutated in situ; both approaches are, again, already close to being technically feasible in mice.

Talks on this topic at IABG 10:
de Grey

Aubrey de Grey's publications on this topic

Mitochondrial mutations and how to obviate them

The mitochondrion is a machine within the cell that does the chemistry of breathing. That is, it takes oxygen and chemically combines it with energy-rich nutrients from our food, to make carbon dioxide and water (which we exhale) and ATP, the "energy currency" of the cell.

The mitochondrion is therefore a really essential part of the cell. Lots of other parts of the cell are essential too, though, so why have a whole SENS page on it? The answer is: unlike any other part of the cell, mitochondria have their own DNA. This means that they can stop working as a result of mutations. Because the DNA is in a different place than the rest of the cell's DNA (which is in the nucleus), we need a different system to combat the inevitable accumulation of such mutations.

As usual, we're lucky - evolution has done the hardest part of this for us already. Mitochondria are very complex -- there are about 1000 different proteins in them, each encoded by a different gene. But nearly all of those genes are not in the mitochondrion's DNA at all! -- they are in the nucleus. The proteins are constructed in the cell, outside the mitochondrion, just like all non-mitochondrial proteins. Then, a complicated apparatus called the TIM/TOM complex (no kidding...) hauls the proteins into the mitochondrion, through the membranes that make its surface. Only 13 of the mitochondrion's component proteins are encoded by its own DNA.

This gives us a wonderful opportunity: rather than fixing mitochondrial mutations, we can obviate them. We can make copies of those 13 genes, modified in fairly obvious ways so that the TIM/TOM machinery will work on them, and put these copies into the chromosomes in the nucleus. Then, if and when the mitochondrial DNA gets mutated so that one or more of the 13 proteins are no longer being synthesised inside the mitochondria, it won't matter -- the mitochondria will be getting the same proteins from outside. Since genes in our chromosomes are very, very much better protected from mutations than the mitochondrial DNA is, we can rely on the chromosomal copies carrying on working in very nearly all our cells for much longer than a currently normal lifetime.

This project needs a lot of work, though, even though it sounds simple. The 13 proteins of interest are actually quite difficult for the TIM/TOM machinery to process even when we "tell" it to do so, so we still need to work on making that part easier. But there has been good progress in this area in the past couple of years.

Talks on this topic at IABG 10:

Aubrey de Grey's publications on this topic

Intracellular junk and how to get rid of it

Cells have a lot of reasons to break down big molecules and structures into their component parts, and a lot of ways to do so. Unfortunately, one of the main reasons to break things down is because they have been chemically modified so that they no longer work, and sometimes these chemical modifications create structures that are so weird that none of the cell's degradation machinery works on them. This is very rare, but in the long run it adds up. The place where it adds up is called the lysosome, a special vessel that contains the most powerful degradation machinery in the cell; if something can't even be broken down there, it just stays there forever. This doesn't matter in cells that divide regularly, because division dilutes the junk away, but non-dividing cells gradually fill up with this stuff -- different types of stuff in different types of cell. The heart, the back of the eye, some nerve cells (especially motor neurons) and, most of all, white blood cells trapped within the artery wall all suffer from this. Eventually these cells can't take any more and they stop working right. This is the sole cause of atherosclerosis (the formation of lumps, called plaques, in the artery wall, which eventually burst and cause heart attacks and strokes). It is also important in several types of neurodegeneration and in macular degeneration (the main cause of blindness in the old). So it's very important to fix it.

So what's the solution? The most promising approach, in my view, is to enable cells to break the junk down in situ so that they don't fill up after all. This can be accomplished by giving the cells extra enzymes that can degrade the relevant material. The natural place to seek such enzymes is in soil bacteria and fungi, as these aggregates, despite not being degraded in mammals, do not accumulate in soil in which animal carcasses are decaying, nor in graveyards where humans are decaying. Preliminary work in my department in Cambridge has already confirmed this optimism. The concept is a logical extension of the replacement of a natural lysosomal enzyme in people who are congenitally deficient for it, something that is already being done. Such deficiencies cause lysosomal storage disorders, such as Gaucher's disease, and replacement of the gene is an effective treatment. Gene therapy is still in its infancy, and its difficulty must not be underestimated, but progress is steady; it may not be overoptimistic to predict that by the time we have identified enzymes capable of degrading lysosomal junk and made them work in mice, gene therapy will be sufficiently advanced to allow their use in humans. Also, very importantly, the biggest application of this technology doesn't need gene therapy at all, because the cells that need to be given the microbial genes are macrophages, special white blood cells, which come from the bone marrow. So we can make the necessary changes to blood stem cells in the laboratory, and then give them to people as a bone marrow transplant, which is much, much easier than gene therapy.

We need a lot more work on this project. It will take time to find the right enzymes in the soil microorganisms, to find the ones that work well in mammalian cells and are not toxic, to modify them so that the cell knows how to target them to the lysosome, and so on. This is a project that is very "parallelisable" -- if lots and lots of laboratories work on it, it will succeed sooner.

Talks on this topic at IABG 10:

Aubrey de Grey's publications on this topic

Extracellular junk and how to get rid of it

Extracellular junk is different from extracellular cross-linking -- it means aggregates of stuff that do not have any function (not even a biophysical one) and should ideally have been destroyed, but have proven resistant to destruction. There are two main examples of such junk. One is the acellular lipid core of mature atherosclerotic plaques, but that doesn't really count, because macrophages are constantly arriving and eating bits of that core, and the only problem is that they can't then break it down after eating it, and eventually they die and become part of the problem. So this would be completely fixed if we could make the intracellular degradation machinery more powerful, as explained here. The other big problem of extracellular junk is called amyloid. Amyloid forms into big globules called plaques in the brain of Alzheimer's disease patients, and the same thing happens (more slowly) in everyone's brains. We don't actually yet know for sure that amyloid is what makes Alzheimer's sufferers lose cognitive function, but we can be pretty sure that the plaques aren't doing any good (though some researchers think that the individual protein molecules do do some good before they aggregate into plaques), so to be on the safe side we should try to get rid of them.

A strategy for indefinitely postponing the accumulation of such material is being pursued by Elan Pharmaceuticals: vaccination to stimulate the immune system (specifically, microglia) to engulf the material. When it has been internalised, it may still be resistant to degradation, but if so its degradation can be achieved by the approach necessary for naturally intracellular aggregates described here. The early clinical trials of the Elan vaccine had to be stopped prematurely because of side-effects, but they're working on a better vaccine.

Another strategy is to use small molecules to dissolve the plaques. It seems that the surface of the plaque can be disrupted by small peptides that winkle their way into it, and this makes it less stable, so whole protein molecules float off the surface. These small peptides are called beta-breakers.

Talks on this topic at IABG 10:

Extracellular protein crosslinks and how to get rid of them

All the proteins inside our cells are destroyed and rebuilt quite regularly, as a way to keep them in a generally undamaged state. Some of the proteins outside our cells, however, are laid down early in our life and then never recycled at all, and some others are only recycled very very slowly. These long-lived proteins are susceptible to chemical reactions. Luckily, the function of long-lived proteins tends to be very simple -- they don't catalyse chemical reactions, for example, the way that enzymes do. In general they have a biophysical function -- they give a tissue elasticity (as in the artery wall) or transparency (as in the lens of the eye) or high tensile strength (as in ligaments). Occasional chemical reactions with other molecules in the extracellular space don't affect these functions very much -- at first. But in the long run, they can matter a lot, especially in the case of the artery wall, which becomes much more rigid and leads to high blood pressure. The type of chemical reaction that causes this loss of elasticity is one that results in a chemical bond (a cross-link) between two nearby proteins that were previously able to slide across or along each other.

Luckily, it happens that a lot of the cross-links that accumulate in this way have very unusual chemical structures, not found in proteins or other molecules that the body makes on purpose. This means that it is theoretically possible to identify chemicals that can react with the cross-links and break them, without reacting with anything that we don't want to break. And indeed, several years ago a group of chemists found such a molecule, which has now been tested in many different animals and also in humans and seems to lower blood pressure quite substantially. These chemists formed a company (named Alteon) to market the drug (named ALT-711), but it is still in clinical trials.

We need more work in this area. There are plenty of other types of cross-link that ALT-711 doesn't break, so we need other chemicals that will complement what ALT-711 does. Some such crosslinks are probably too stable to be breakable catalytically by any non-toxic small molecule; here it may be necessary to find enzymes that can couple the link-breakage to hydrolysis of ATP (which might need the enzyme to shuttle back and forth across the cell membrane, as there is very little ATP in the extracellular space) or else to use the concept of "one-shot" proteins, such as the DNA repair protein ATase, which react with a stable molecule but thereby inactivate themselves. This is a feasible approach because of the very low rate of formation of the relevant cross-links: the cellular energy budget would not be significantly impacted.

Talks on this topic at IABG 10:

Further References:

Alzheimer A. Uber eine eigneartige Ehrankung der Himrinde. Allg Z Psychiatr Psychish-Gerichtliche Med 1907; 64:146-148.

Brody H. Organization of the cerebral cortex III. J Comp Neurol 1955; 102:511-556.

Szilard L. On the nature of the ageing process. Proc Natl Acad Sci USA 1959; 45:35-45.

Strehler BL, Mark DD, Mildvan AS, Gee MV. Rate and magnitude of age pigment accumulation in the human myocardium. J Gerontol 1959; 14:430-439.

Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 1965; 37:614-636.

Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc 1972;20:145-147.

Monnier VM, Cerami A. Nonenzymatic browning in vivo: possible process for aging of long-lived proteins. Science 1981;211:491-493.

Cutler RG. The dysdifferentiation hypothesis of mammalian aging and longevity. In: The Aging Brain: Cellular and Molecular Mechanisms of Aging in the Nervous System (Gicobini E et al., eds), Raven (New York), 1982, pp. 1-19.

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