Future Tense

Rejuvenation Biotech

Can regenerative medicine defeat aging?

This piece arises from Future Tense, a collaboration among Arizona State University, the New America Foundation, and Slate. A Future Tense conference on life extension will be held at the New America Foundation on Tuesday, Nov. 16. (For more information and to sign up for the event, please visit the NAF Web site.) Read more of Slate’s coverage on longevity.

Grandmother. Click image to expand.
How can we keep grandma young?

Aging is bad for you. Whether you call it a disease, not a disease, a set of disease precursors, or some other variation on the theme, it is a medical condition, and thus a legitimate target—in principle—for medical intervention.

But is it a practical target? Medicine generally targets individual problems—a particular strain of virus, for example, or damage to a particular area of flesh. Aging seems like a huge number of progressive, chronic diseases all interacting with one another. Might such complexity be beyond the power of medicine—even medicine decades hence—to address?

Once these progressive, chronic diseases have become debilitating, piecemeal targeting of them is far less effective than medicine generally is against other, aging-independent diseases. The complexity is bad enough, but what’s worse is that the diseases are progressive—they get harder to treat as time goes on, because they are simply the later stages of intrinsic, lifelong processes of accumulation of molecular and cellular damage.

Is there a way out? Biologists who study aging have long been impressed by the fact that aging seems orchestrated, and especially that the one manipulation that reliably postpones aging in laboratory animals—calorie restriction—is a very simple intervention that nonetheless elicits all the metabolic changes required to postpone age-related ill-health and extend life. This, the reasoning goes, suggests that medical interventions against aging could likewise be simpler than the phenomenon they target. But there are also persuasive counterarguments. First, the efficacy of calorie restriction is an exception, highly unlikely to be repeated by other simple interventions (except those that mimic it). Second, it is likely to work far less well in long-lived species such as humans than in mice or rats. And these arguments are robustly supported by available data.

However, in the past decade a new approach to medical intervention in aging has been explored: regenerative medicine. The attraction of this approach is that it acknowledges the irreducible complexity of aging but attacks the problem more pre-emptively than contemporary geriatric medicine does. Regenerative medicine can be defined as the restoration of structure to any damaged tissue or organ. As such, it encompasses molecular, cellular, and organ-level repair. As applied to aging, it amounts to preventative maintenance: periodic partial elimination of the accumulating damage of aging before that damage reaches a pathogenic level, thus postponing, maybe indefinitely, the age at which the ill-health of old age emerges.

OK, so it’s an interesting new approach. But is it actually promising? Here’s a selection of the reasons for optimism.

The classical areas of regenerative medicine have been moving ahead at an unprecedented pace in recent years. Some of the highlights have, with good reason, been celebrated in the mainstream media: The foremost example is the development by Shinya Yamanaka, and subsequent refinement by numerous groups, of a method to convert adult cells into a state very similar to embryonic stem cells. These cells, termed “induced pluripotent stem cells” or iPS cells, appear to have almost all the versatility of true embryonic stem cells, but can be obtained far more easily, in far greater numbers, and without the main ethical challenges that have confronted the embryonic stem cell field.

Less celebrated, but possibly of similar significance, is an advance in tissue engineering. Following the pioneering work of Doris Taylor, many groups are now pursuing a creative solution to the main problem that has always dogged tissue engineering: vascularization. The blood supply is a vital component of any solid organ, and it has proved hugely difficult to cajole the body to create a competent vasculature in an artificial organ before the cells in that organ have succumbed to deprivation of oxygen or nutrients. Taylor’s solution is to “decellularize” an organ from another individual—possibly not even from a human—leaving only the extracellular matrix that defines the vasculature, and then to repopulate this scaffold with suitable cells typically taken from the intended recipient of the organ. This achieves the main goal of tissue engineering, the rejection-free replacement of a damaged organ.

Less conspicuous is “molecular regenerative medicine”— repair of the intracellular structure of live cells in situ, or of extracellular structures, as opposed to the wholesale replacement of cells or organs. One of the most impressive advances within this field relates to Alzheimer’s disease. The amyloid plaques that accumulate in the brains of Alzheimer’s sufferers can be removed by vaccination, a trick that was first demonstrated (in mice) a decade ago. Doubts surfaced thereafter concerning whether this could work in humans, but the approach looks promising at present, with clinical trials having progressed to Phase III. Removal of plaques is unlikely to constitute a complete cure for Alzheimer’s disease, but it is almost certain to be part of an eventual combination treatment.

At an earlier stage, but still immensely exciting, is the corresponding treatment for “molecular garbage” that accumulates not between cells but inside them. This is a more challenging aspect of aging, because the material in question is resistant to breakdown by any human enzymes. The solution being pursued by the SENS Foundation, the charity of which I am the chief science officer (SENS stands for Strategies for Engineered Negligible Senescence), is to identify non-human enzymes that can do the job and introduce them into our cells. The biggest initial challenge is to identify such enzymes, but we have now done that with respect to the main types of garbage responsible for cardiovascular disease and macular degeneration. This has already led to several peer-reviewed academic publications, and we hope to bring it to the stage of testing in mice within the near future.

Additional targets being pursued by SENS Foundation include the elimination of cells that refuse to die when the body wants them to—a major aspect of the decline of the immune system with age, among other things—and the

prevention of mitochondrial mutations by putting modified copies of the mitochondrial DNA into the nucleus.  These projects are moving forward with impressive speed, though slowed by resource limitations.

When all these components are combined, will we have bona fide rejuvenation biotech? We won’t know that for certain until we complete the development of all those components, at least in mice. But every type of “aging damage” of which we’re aware—and for which SENS Foundation and others are developing interventions—has been known about for well over a quarter of a century. If some other factor is at work in aging, then biologists should have identified it by now. It looks as though all that stands between us and control of aging is hard work. Let’s up the pace.

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