Proposing Combination Gene Therapy to Slow Aging
There are all sorts of longevity-associated genetic manipulations either demonstrated or postulated to produce benefits in mice. Why not try them all at once to see what happens? If you think that slowing aging through alteration of metabolism to reduce the impact of the cellular and molecular damage that causes aging is a useful strategy, or you believe that aging is programmed and not actually caused by damage, then this is an ambitious (though possibly overoptimistic) plan of exploration that wouldn't require more than a few million dollars to carry out.
To my eyes, however, this is merely a way to spend more money avoiding the better approach of repairing that damage. Slowing aging - slowing down damage - won't benefit the old who are already heavily damaged, and it won't produce as large an effect as repairing that damage. Yet it will be much more expensive and complicated: researchers have made only small inroads into sufficient understanding of metabolism and aging in detail to know how to make safe alterations, and can't even yet fully explain how natural age-slowing processes such as calorie restriction work, but we already have a comprehensive research program for repair planned out and know more than enough to steer it to near completion. Time is ticking and we don't have the luxury of being able to spend more to produce less when it comes to treatments for degenerative aging.
This research proposal comes from scientists associated with the Russian language advocacy community and the Science for Life Extension Foundation. They have had some success in the last few years raising funds from the community for smaller projects with mice, and may manage to get this funded the same way:
We propose developing a gene therapy that will radically extend lifespan. Genes that promote longevity of model animals will be used as therapeutic agents. We will manipulate not a single gene, but several aging mechanisms simultaneously. A combination of different approaches may lead to an additive or even a synergistic effect, resulting in a very long life expectancy.11 genes that are most promising in terms of life extension will be used as targets for gene therapy. We will affect both the biological aging mechanisms, common to all the cells of the organism, as well as the primary neuroendocrine center, that regulates the whole organism's longevity - the hypothalamus. The expression increase or decrease of these genes in animal models was shown to result in boosted longevity. If the increase in expression of a particular gene is necessary for longevity, we will deliver this gene into the body. If, on the other hand, longevity depends on the inhibition of a certain gene's expression, we will introduce a genetic construct that encodes small RNAs that inhibit the expression of the target gene.
In addition, we will deliver 8 genes that prevent the individual tissue function disruption in old age. Each of these genes separately has previously been successfully used for gene therapy of one of the age-related diseases in rodent models.
All groups of mice will be regularly tested for aging markers, and also the blood and adipose tissue transcriptome, proteome and metabolome will be analyzed. All age-related histological and physiological changes will be studied. Behavioral test will be performed to analyze cognitive ability and locomotor activity in mice. The average and maximum lifespan of mice will be determined. In addition, a detailed study of side effects will be performed. Mice will be compared with old mice of the control group as well as with young mice.
I'm just a layman, but I agree with Reason's logic (assuming accumulated damage is the cause of aging) that this is a dead end which will not benefit the old, and will only marginally benefit the young (and only if the complexity of metabolism doesn't keep throwing a spanner in the works via unexpected side effects).
Still, sometimes you have to fail faster to realize that the path you are on is the wrong one. Hopefully the clever people backing this approach will eventually realize that trying to manipulate metabolism is fairly fruitless switch to a damage repair based approach to rejuvenation biotechnology. On the other hand, David Sinclair and his group are clearly highly capable researchers, yet they are still continuing to pursue Sirtuins all these years later.
I've heard David Sinclair talk about the difficulties of some aging research i.e. removing misfolded proteins. This struck me as highly unusual because those things are already in drug development for humans whereas his ideas are still a long way off.