Fight Aging!

The next logical step for researchers after discovering a range of different ways to slow aging in laboratory animals is to try these methodologies in combination. Many in fact work to extend healthy life through overlapping mechanisms, and so much of the incentive for the researchers is not in fact to produce greater extension of longevity, but rather to get a better handle on which of these methods of life extension are just different ways of triggering the same underlying processes.

Some years ago, researchers demonstrated a tenfold increase in life span in nematode worms. Short-lived lower animals have so far shown a much greater potential extension of life than longer-lived higher animals; for example the record in mice is only a 60-70% extension of life span, even though very similar approaches are presently used to alter metabolism to enhance longevity in species such as worms, flies, and mice. In humans we'd expect the benefits to be much smaller again: the equivalent natural mutants in human populations don't appear to live longer than the rest of us, although studies suggest that they are more resistant to some age-related disease.

That tenfold increase in nematode life spans was achieved through a single gene mutation in the insulin / insulin-like growth factor 1 pathway. Here, however researchers achieve a fivefold increase by combining methods that individually produce smaller gains:

Five-Fold Lifespan Extension in C. Elegans by Combining Mutants

What are the limits to longevity? New research in simple animals suggests that combining mutants can lead to radical lifespan extension. [Scientists] combined mutations in two pathways well-known for lifespan extension and report a synergistic five-fold extension of longevity in the nematode C. elegans.

The mutations inhibited key molecules involved in insulin signaling (IIS) and the nutrient signaling pathway Target of Rapamycin (TOR). Single mutations in TOR usually result in a 30 percent lifespan extension, while mutations in IIS (Daf-2) often result in a doubling of lifespan in the worms - added together they would be expected to extend longevity by 130 percent. "Instead, what we have here is a synergistic five-fold increase in lifespan. The two mutations set off a positive feedback loop in specific tissues that amplified lifespan."

The positive feedback loop (DAF-16 via the AMPK complex) originated in the germline tissue of worms. The germline is a sequence of reproductive cells that may be passed onto successive generations. "The germline was the key tissue for the synergistic gain in longevity - we think it may be where the interactions between the two mutations are integrated. The finding has implications for similar synergy between the two pathways in more complex organisms."

The germline connection is interesting, as other researchers have shown that life can be extended in nematodes via removal of the germline, or genetic manipulations primarily focused on germline cells.

These pioneering demonstrations of life extension in the laboratory by slowing aging have, I think, little direct relevance to the future of human life extension. They are principally important for the continued accumulation of knowledge regarding metabolism and aging. Development of means to slow aging in humans isn't a good path from a practical point of view: it is very challenging, very expensive, and the safe adjustment of metabolism will require far more knowledge than is presently available to the research community, even when the goal is only to replicate known beneficial metabolic alterations such as the response to exercise or calorie restriction. The result at the end of the day - therapies to slow the course of aging - will be of little use to old people, despite the fantastic cost it will require to get to that point.

This is why it is important to look past much of this work on slowing aging, and the media attention it obtains, and focus instead on repair-based strategies such as SENS research. We will only be able to meaningfully help the aged - ourselves in a few decades, in other words - by developing rejuvenation therapies, not just means to slightly slow down the aging process. To rejuvenate the old, to reverse aging, requires a focus on repair of the known and cataloged forms of damage that cause degeneration: the research community can do that with the metabolism we have, with no need to engineer a new one. Further, far more is known of what has to be done than is the case for the metabolic manipulation approach to slow aging.