Friday, March 01, 2013

Should We Prevent Disease, or Slow Down Aging?

In previous posts I've talked a lot about mortality statistics and life expectancy, and gave a lot of reasons why the strategy of extending life by identifying, then curing or eliminating, one by one, the various known major causes of death (heart disease, cancer, diabetes, etc,) is probably a wrongheaded way to go. For example, I mentioned that total elimination of all forms of cancer would increase overall life expectancy by only three years. That's no reason to stop working on a cure for cancer, of course. We definitely should try to cure cancer, as a way to prevent needless suffering (but not as a way to obtain a major increase in life expectancy). To increase life expectancy in any kind of meaningful way, we have to do more than come up with newer/better cancer therapies.

Our basic task should be to figure out why and how cells and bodies age and die. This is our best hope at extending life expectancies. In other words, we should start from the hypothesis (well supported by observation) that organisms have a tendency to age and die no matter which diseases they get or don't get. If we can conquer or at least greatly slow the basic process(es) of senescence, maybe diseases like cancer won't be significant hazards until a person is, say, 150 or 200 years old, instead of 40, 50, 60, etc. years old. That should be the real goal. Get cancer at 150, not 50.

What do we know about senescence? Lots of bits and pieces. We know how to knock out various genes in fruit flies, for example, to make them live twice as long. But we still don't have a comprehensive theory of aging.

The major lines of research tend to focus on a just a handful of ideas. It's best not to think of these ideas as competing (mutually exclusive) theories. It's not like one of them will be declared "the winner" and the rest will be discredited. The major contenders are:
  • The cross-linking/glycation theory
  • The neuroendocrine theory
  • The free-radical theory
  • Telomere theory (replicative endpoint theory)
  • The genome and protein maintenance theory
There's yet another theory, that organisms have death "programmed in," such that when a certain point is reached in old age, a well-ordered shutdown process is triggered. This apoptosis theory isn't really adequate to explain senescence (which is by nature gradual) and thus isn't really an aging theory per se, even though we know that apoptosis mechanisms do exist. Current thinking is that, at a cellular level at least, apoptosis is mainly a cleanup mechanism to stop defective cells (such as cancer cells) from reproducing.

Let's go through the major theories one by one.


Evidence for the cross-linking theory consists of the observation that over time, proteins (and certain other molecules) sometimes link to each other, covalently, either via sulfide bridges or through a process called glycosylation or glycation. Glucose molecules can stick to proteins, then transform into brownish molecules called advanced glycosylation endproducts, or AGEs. We know that cross-linking of collagen occurs in wrinkled skin, and it's possible cross-linking of proteins in the lens of the eye plays a role in cataract formation. It's been speculated that cross-linking plays a role in atherosclerosis and age-related decline in kidney function. Good evidence has emerged that AGEs play a role in pathogenesis of Alzheimer's disease as well as diabetes. In fact, work on AGEs and Alzheimer's disease has led to so many complementary findings that some researchers have begun referring to Alzheimer's Disease as "Type 3 diabetes."

Neuroendocrine Theory
The neuroendocrine theory of aging says that many aging processes start with the changes in hormone levels that come about late in life, triggered by processes deep within the brain. This theory almost died at one point, due to contradictory lines of evidence, but it has come back from the dead based on strong findings having to do with the insulin/IGF-1 hormonal pathway. IGF stands for insulin-like growth factor, a substance activated by growth hormone. In all laboratory organisms studied thus far (from fruit flies to worms to rodents), mutations that reduce the amount of circulating IGF extend life. Also, several varieties of dwarf mice lacking growth hormone (GH), prolactin (PRL), and/or thyroid-stimulating hormone (TSH), live much longer than their normal siblings and exhibit many symptoms of delayed aging. (See here and here.) 

Free Radicals
The free-radical hypothesis says that free radicals (whether originating endogenously via enzyme action, or through spontaneous chemical processes) are the source of most of the oxidative damage that tends to build up in tissues over long periods of time. Oxidative damage is associated with many disease processes, and in fact one of the weaknesses of the free-radical hypothesis is that free radicals are so prevalent, so toxic, and can cause so many kinds of damage to so many biological molecules and so many cellular systems, that there's hardly a disease that can't be explained away by a wave of the free-radical wand. It hasn't been a terribly helpful theory for making predictions. Health-food advocates have been saying for years that the best way to limit free-radical damage in your body is to eat antioxidants, but there's a difference between inhibiting redox reactions and scavenging free radicals, and the idea that any particular food can selectively target free radicals is a bit fanciful, to say the least. (A huge and largely contradictory literature exists on the subject; see this Wikipedia article and its 245 references.) None of this, of course, has kept food companies from trumpeting "Rich in Antixodants!" on food packaging. (They might just as well trumpet the use of preservatives. Most food preservatives are, in fact, antioxidants.)

Nonetheless, it's interesting that fruit flies raised in a 100% oxygen atmosphere tend to start dropping like (what else?) flies at very early ages. It's also interesting that some of the longest-lived humans in the world tend to live at high altitudes (where oxygen is in short supply). It turns out there's good evidence that mitochondria (organelles specifically concerned with respiration) are heavily involved in processes that affect aging, and as it happens, mitochondria are hotbeds of free-radical activity. In fact, at this point it could be said that the free-radical theory of aging has effectively transformed to the Mitochondrial Theory of Aging. For a somewhat technical look at the free-radical theory of aging, I recommend Ben Best's post on the subject. Mr. Best also has a fine discussion of antioxidants and aging here.

Telomere Theory
In contrast to most other theories of aging, telomere theory is elegant, easy to summarize, and well validated experimentally. In 1961, Leonard Hayflick and Paul Moorhead found that human fibroblasts tend to undergo a fixed number of doublings (typically 40) when grown in vitro; then they stop and die. The cells seem to remember their generation number and die when the number of ancestor generations reaches a certain limit, now known as the Hayflick Limit. The Hayflick limit was eventually explained in terms of how telomeres work. Basically, telomeres are like the little plastic tubes on the ends of shoelaces, without which the lace-ends fray, except telomeres occur at the ends of chromosomes. They're non-gene-encoding "starter regions" in the DNA, designed to help set up the machinery of replication. Due to the way DNA replication works, every new copy of DNA is very slightly shorter than the ancestor copy that preceded it. After many copies of copies of copies have been made, the end of the DNA is shortened so much that further copying will lead to (potentially disastrous) gene truncation, because there's not enough telomere DNA at the end to allow proper priming of the copying process. (See big tall graphic.) Therefore, to avoid disaster, cell division must stop after a certain number of chromosome replications, unless (of course) telomeres can somehow be replenished in the meantime. It turns out there's an enzyme just for that purpose, telomerase, which is indeed able to restore the "starter region" on the DNA (the plastic thingy on the end of the shoelace). When telomerase is allowed to replenish a chromosome's telomeres endlessly, the cell becomes immortal. In some cases, that means it becomes cancerous.

Needless to say, considerable research effort is being devoted now to telomeres and telomerase, to see how telomerase can be modulated in ways that might cure cancer and/or lengthen life expectancy of otherwise-healthy cells. We do know that human telomeres tend to shorten with age and that people with 'long life" in their families tend to have longer telomeres than most. You can get a feel for where things stand (and where they're headed) in telomere research by consulting the resources listed here.

Molecular Maintenance
Finally, there's the molecular maintenance theory of aging, which says that longevity of cellular machinery depends on keeping the basic macromolecules of life, namely proteins and DNA, in proper working order through continuous damage repair. As with the free radical theory, this is a complex topic, with many interesting aspects to it, and obviously space prohibits anything approaching a useful summary of recent findings here. Suffice it to say much of the relevant research centers around a special class of proteins called chaperones, which are specifically designed to prevent and/or correct protein misfolding. (There are chaperones for the proper folding of histone-DNA complexes as well. RNA chaperones are also known.) Most proteins auto-fold into their correct 3-D conformation at the time of synthesis, but some proteins require help for final "correct" folding. Chaperone proteins provide that help. Chaperones have another important function, which is to refold proteins that have partially denatured through heating. It turns out that with even a modest increase in termperature, many proteins begin to unravel, and once unraveled (even slightly), a protein doesn't automatically know how to refold itself back to the proper conformation. Chaperone systems come to the rescue of such proteins, making it possible for them to regain their proper (original) folding. Because chaperone proteins themselves are upregulated in times of heat stress, chaperone proteins have often been called heat shock proteins, and they have names like Hsp70 and Hsp90.

If you imagine a cell as a big origami factory, turning out intricately folded bits of paper (proteins) that have to be folded "just so" in order to serve their intended purpose, chaperones are the quality-control inspectors that spot a misfolded item and refold it back to its proper form ("just so") so it can once again function properly.

For a review of the possible role of chaperone proteins in fixing cell damage in aging cells, see J. Krøll's (2004) The molecular chaperones and the phenomena of cellular immortalization and apoptosis in vitro, Morley and Morimomo's "Regulation of Longevity in Caenorhabditis elegans by Heat Shock Factor and Molecular Chaperones," (Molecular Biology of the Cell
Vol. 15, 657–664, February 2004), Daniel Herschlag's "RNA Chaperones and the RNA Folding Problem" (September 8, 1995 The Journal of Biological Chemistry, 270, 20871-20874), plus "Aging and molecular chaperones," by Soti and Csermely, Exp Gerontol. 2003 Oct;38(10):1037-40.

With all of this as prelude, we can proceed to a discussion of one of the more fruitful lines of investigation involving anti-aging, something that has a long, well-established basis in scientific research, with clear implications for what you can do today, right now, to begin to increase your lifespan. We'll visit that topic tomorrow.