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Improving Health and Longevity

Developing Biomedical Tools to Repair Molecular and Cellular Damage

Aubrey de Grey
Biomedical Gerontologist
University of Cambridge
http://www.gen.cam.ac.uk/sens/AdGbio.htm

I consider it likely that within the next few decades we will develop the biomedical tools to repair all the major types of molecular and cellular damage that accumulate during life and eventually kill us: in a phrase, to reverse aging. But that reversal will not be complete. All the major types of damage will be reversed, but only partly so. In several cases this incompleteness is because the category of damage in question is heterogeneous, consisting of a spectrum of variations on a theme, some of which are harder to repair than others. In the short term it’s enough to repair only the easiest variants and thereby reduce the total damage load a fair amount, but in the longer term the harder variants will accumulate to levels that are problematic even if we’re fixing the easy variants really thoroughly. Hence, we will have to improve these therapies over time in order to repair ever-trickier variants of these types of damage. I predict that nanotechnological solutions will eventually play a major role in these rejuvenation therapies. Here I briefly describe some categories of age-related damage in which I expect nanotechnology to play a particularly important role.

Infectious diseases

Our immune system is extremely good at getting rid of infections, but viruses and bacteria are also extremely good at evading our immune system: it’s an arms race. If we want to live a really long time, we must do everything we can to augment our immune system to eliminate infections that our natural immune system cannot. This includes both acute infections that kill people quickly and persistent ones that are brought under control by our natural defences but remain present in a latent state and contribute to immune senescence (the decline of efficacy of the immune system with age).

Nanotechnology can potentially improve on anything that biotechnology could to in this regard, because of the structure of infectious agents. Infections come in two main forms: bacterial and viral. Even though by some definitions viruses are not alive, they share with bacteria one key characteristic: their genome is made of nucleic acids. A fundamental limitation of what enzymes can do to the genomes of bacteria and infections is imposed by the length of DNA or RNA sequence that they can recognise as being from the virus or bacterium and not our own. This limitation should be straightforward to overcome using enzyme-sized non-biological structures (which for brevity I will hereafter call "nanobots") that have arbitrarily extensive information (possibly transmitted to them) on what sequences are human and what are not. This will therefore allow such machines to be targeted to DNA or RNA purely on the basis of sequence and without side-effects caused by destruction of human nucleic acids. Thus, these machines can invade all parts of the cell in all tissues, whereas enzymatic or immune defences against infections must be much more cautious.

Cancer

The potential role of nanotechnology in combating cancer is quite similar to its role in combating infectious diseases: it can potentially repair our DNA in cells that have acquired mutations. In this case, however, it is also important to repair "epigenetic" alterations — chemical modifications of DNA or of histones, the proteins around which DNA is wrapped — because these changes determine whether and at what rate particular genes are expressed (give rise to their encoded proteins). This is much harder, because even though all our cells have the same DNA sequence (except for a few special exceptions related to the immune system), the epigenetic state of different cells varies greatly. Moreover, this state cannot be "reset" in a given cell, because it defines the type of cell it is — brain cells express some proteins, liver cells express others, and that difference is a result of these cells’ different epigenetic states.

In due course, we will know enough about the correct epigenetic state of all cell types to be able to reset it using nanobots just as precisely as we can correct DNA sequences or delete foreign ones. But biology is unimaginably complicated, so the preferable approach is to look for solutions that do not require such thorough understanding of what’s "correct". A solution that would seem plausible is to exploit the fact that epigenetic changes, like genetic ones, are random — they have been termed "epimutations". This would allow a statistical approach: a surveying of the cells in a given tissue and identification of ones that have suspicious epigenetic patterns. Interestingly, "suspicious" would probably not be defined simply as "minority", because the cells to be targeted are ones that are dividing more insistently than they are supposed to. So what one would want to look for are statistically implausible similarities between the epigenetic patterns of a group of cells — not even necessarily spatially adjacent cells, as cancers can shed cells into the circulation.

Other nuclear mutations and epimutations

A cell can of course accumulate mutations or epimutations that make it misbehave in ways other than cancer. In the short term this may not be a problem for longevity because the risk of cancer has ratcheted up our natural DNA maintenance and repair systems so well that non-cancer problems — which have to occur in a reasonable proportion of the cells in a tissue, not just in one originating cell — should not occur for many times a currently normal lifetime. But they’ll happen eventually.

Here the solution for mutations is as above, and the solution for epimutations may be similar to the above, but in this case the statistics would be different — we would want to "regress to the mean" and restore patterns present in most cells of the tissue. Here there is a potential challenge in respect of epigenetic changes that occur cyclically, e.g. through the cell cycle, but such changes are probably far fewer in number than those that define the differentiated state — maybe few enough in number that we will by this time have enumerated them fully.

Hardening of elastic structures

Non-genetic changes are also likely to need nanotechnological solutions in due course. Long-lived proteinaceous structures such as the artery wall and the lens of the eye become harder with age because they accumulate random chemical bonds between adjacent proteins. Some of these bonds are unstable enough to be breakable by drugs, one of which is already in clinical trials, but others are much more stable and a drug-based solution is impractical. However, the chemical structures involved are very different from any physiological ones, so enzymes could in principle cleave them without side-effects. The problem then becomes one of coupling the endothermic cleavage of the stable bond to an exothermic reaction: this is challenging, because the usual sources of such energy (ATP and NADH) are virtually absent in the extracellular medium. Nanobots could perhaps solve this problem more easily than enzymes by being designed to shuttle in and out of cells to "recharge".

Dismantling indigestible aggregates

The accumulation of "garbage" inside cells, mainly in the lysosome, is one of the most universal phenomena in aging: it is seen in all species that have non-dividing cells. As with extracellular crosslinks, the problem is one of the unavailability of enzymes that cam destroy the material, and such enzymes should in theory exist. However, as in the extracellular space there is a shortage of ATP. Also, since enzymes are proteins, they are quite rapidly degraded by the lysosomal proteases that are there to destroy other proteins. Nanobots would seem to be the ideal solution to this latter problem, and the ATP supply problem can be addressed by shuttling between compartments as above.

Web resources

Web resources concerning these problems and the potential biotechnological and nanotechnological solutions to them include the following:

Strategies for Engineered Negligible Senescence
http://www.gen.cam.ac.uk/sens/
Site related to Rob Freitas’s Nanomedicine books
http://www.nanomedicine.com/

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