Philanthropy by high net worth individuals has the potential to move the needle on any major biotechnology project these days. The cost of research in the field is falling rapidly, thanks to spectacular ongoing gains in computational power and materials science. There are now thousands of individuals in the world with a net worth sufficient to completely fund a cure for a disease, from a starting point of nothing but ideas through to first human trials. But of course to exchange your entire net worth for a cure, to give up on the whole of the vast process that has been your business life to date, you'd have to be something of a visionary zealot - and people tend not to be both very wealthy and visionary zealots of this nature; the two paths are mutually exclusive.

The cost to develop the various biotechnologies of rejuvenation enumerated in the SENS vision - a digest of discoveries from the past twenty years in many fields of the life sciences, coupled with innovative, detailed plans to develop therapies - might be in the vicinity of a billion dollars over ten to twenty years. That would give you a good chance at demonstrating rejuvenation in old mice, such as by doubling their remaining life span, with commensurate improvements in their health and reductions in risk of age-related disease. There are perhaps a hundred people in the world who could fund that project end to end on 10% of their net worth or less, though as I've noted in the past a billionaire is possibly best viewed more as the head of a city-state than a person with complete agency over their own fortune.

One portion of the advocacy and fundraising for new approaches to longevity science like SENS involves gathering a strong grassroots community and leaning on their modest financial support. This sort of activity typically takes place during the bootstrapping phase of development, and in the process validates your cause in the eyes of established funding sources, high net worth philanthropists, and so forth. These institutions and individuals tend to be very conservative in how they devote their resources to scientific projects, which means that you must have some backing and widespread validation in order to become an attractive recipient. So it has traditionally been the case that you can't really make too much of a mark without both a broad base of support among the public and interested followers, and then atop that some circle of people and institutions capable of devoting large-scale funding to solving specific problems. The rise of crowdfunding is changing that balance, but it still generally holds - it's the rare organization that manages to skip past the need for wealthy donors due to the size and strength of its community.

Given all of this you might look at the advocacy and outreach for SENS or other disruptive, next-generation, high-yield approaches to extending healthy human life as something that has three components:

• Convince the scientific community.
• Convince the general public.
• Convince high net worth donors and funding institutions.

In the third category, there is the constant process of networking - connections, discussions, and introductions that we don't see all that much of from the outside - but there is also the matter of messaging via channels aimed at the wealthier and more influential portions of society. One example of that is a recent article by researcher and advocate Aubrey de Grey in the Private Journey, a magazine aimed at luxury consumers. Via the Reddit SENS community, I note that a PDF copy can be downloaded from the SENS Research Foundation site archives:

The Undoing of Aging

The desire to defeat aging is surely even more long-standing than the quest to reach the stars. Unfortunately, the idea that we will crumble and die is so crippling that most people evidently need to convince themselves, by whatever means, that it is not such a bad thing after all. Whether it's the existence of a joyous afterlife, or the presumption that a post-aging world would be unsustainably overpopulated, or the fear of immortal dictators, a conversation with nearly anyone about the idea of developing medicine to prevent age-related ill-health is almost certain to be derailed into arguments about whether such medicine would be a good thing at all.

A key pillar of many people's thinking about this topic is the misconception that "aging itself" is somehow a different sort of thing than the diseases of old age. There is actually no such distinction. Age-related diseases spare young adults simply because they take a long time to develop, and they affect everyone who lives long enough because they are side-effects of the body's normal operation rather than being caused by external factors such as infections. In other words, aging is simply the collection of early stages of the diseases and disabilities of old age, and treatment of aging is simply preventative medicine for those conditions - preventative geriatrics. It is thus logically incoherent to support medicine for the elderly but not medicine for aging.

I claim no originality for the above: it has long been the virtually universal view of those who study the biology of aging. I believe it is resisted by the wider world, despite those experts' energetic efforts, overwhelmingly because people don't believe there is much chance of significant progress in their or even their children's lifetimes and they don't want to get their hopes up. But in recent years, the justification for such pessimism has evaporated.

It has done so above all because of progress in regenerative medicine, which colloquially (but see below) consists of stem cells and tissue engineering. Regenerative medicine can be defined as the restoration of bodily function by restoration of structure. We may replace entire organs (tissue engineering), or we may repair organs by replacing their constituent cells (stem cell therapy). In a sense, regenerative medicine is maintenance for the human body. as such, it should in principle be capable of constituting preventative maintenance for the chronic, slowly progressive, initially harmless but eventually fatal processes that jointly make up aging and the diseases of old age. Regenerative medicine has only recently, however, become recognized as a promising avenue for postponing age-related ill-health. This is for two reasons. firstly, it was originally conceived and pursued for its potential to treat acute injury, such as spinal cord trauma, rather than chronic damage: thus, regenerative medicine pioneers and biologists of aging simply didn't talk to each other very much, with the result that those studying aging were insufficiently informed about progress in regenerative medicine to appreciate its potential. The second reason was equally important: in order to be plausibly applicable to aging, regenerative medicine must be broadened into a host of other areas, over and above stem cells and tissue engineering, and those areas are mostly at considerably earlier stages of development.

But not fancifully early. In the decade since I first laid out a putatively comprehensive classification of the various types of molecular and cellular "damage" that must be periodically repaired in order to stave off the decline of old age, and the specifics of how we might do it, progress has been gratifyingly rapid (though I estimate it could be at least three times faster if the potential of this approach were more widely understood and funding for it correspondingly elevated). Furthermore, that plan has abundantly stood the test of time, undergoing only minor adjustments.

In this short, general-audience piece I can only hint at the advances over the past year or two achieved by researchers worldwide in this space. SENS Research Foundation was created for this purpose, and alongside numerous other institutes and organizations, both commercial and nonprofit, we have achieved not only the retardation of aging but its actual repair, restoring youthful health to animals that were suffering widespread age-related decline. Much remains to be done to extend these results, before they can realistically be applied in the clinic. However, the removal of toxic metabolic by-products shows clear promise of completely eliminating cardiovascular disease, the Western world's foremost killer, and also macular degeneration, the leading cause of blindness in the elderly. Similarly, removing cells that have become dysregulated and toxic to the body was recently shown, in multiple models, to restore function to sick animals. Advances like these, in combination with traditional regenerative medicine, may in the next few decades deliver a truly comprehensive and dramatic postponement of age-related ill-health.

Source:
http://www.fightaging.org/archives/2013/04/aubrey-de-grey-on-the-undoing-of-aging.php

Many longevity mutations discovered in lower animals such as nematodes involve alterations to mitochondrial function - which only reinforces the apparent importance of mitochondria in determining life span. Mitochondria swarm within cells, working to produce the chemical energy stores used to power cellular operations. In doing so they emit reactive oxygen species, however, that can cause all sorts of harm to the molecular machinery of a cell if not neutralized by a cell's native antioxidants. It is damage to mitochondrial DNA, however, that seems to be one of the root causes of degenerative aging, via a Rube Goldberg sequence of consequences that causes cells to become dysfunctional mass exporters of reactive, harmful molecules.

From a practical therapy standpoint, the research community should be working on ways to repair, replace, or back up mitochondrial DNA in our cells if we want this contribution to aging to go away. That work is very poorly funded, however, in comparison to the benefits it might deliver. Meanwhile, examination of longevity mutations in lower animals continues to reinforce the fact that this is an important direction for therapies to treat and reverse aging.

Some mitochondrial longevity mutations work via hormesis; they cause a slight increase in the level of emitted reactive oxygen species, which in turn causes the cell to react with increased housekeeping and repair activities, resulting in a net gain - less damage over the long term translates into slower aging. Other mutations lower the level of emitted reactive oxygen species, which again means less damage over the long term. Yet more mitochondrial mutations extend life in less obvious ways, or cause mitochondrial dysfunction that appears at the high level to be broadly similar to that of longevity mutants, yet reduces life span. Once you start digging in to the mechanisms of the mitochondrial interior - the electron transport chain with it's multiple complexes - it's all far from simple

Here is an example of research into the mechanisms of mitochondrial longevity mutations in nematode worms:

Many Caenorhabditis elegans mutants with dysfunctional mitochondrial electron transport chain are surprisingly long lived. Both short-lived (gas-1(fc21)) and long-lived (nuo-6(qm200)) mutants of mitochondrial complex I have been identified. However, it is not clear what are the pathways determining the difference in longevity.

We show that even in a short-lived gas-1(fc21) mutant, many longevity assurance pathways, shown to be important for lifespan prolongation in long-lived mutants, are active. Beside similar dependence on alternative metabolic pathways, short-lived gas-1(fc21) mutants and long-lived nuo-6(qm200) mutants also activate hypoxia-inducible factor-1? (HIF-1?) stress pathway and mitochondrial unfolded protein response (UPRmt).

The major difference that we detected between mutants of different longevity is in the massive loss of complex I accompanied by upregulation of complex II levels, only in short-lived, gas-1(fc21) mutant. We show that high levels of complex II negatively regulate longevity in gas-1(fc21) mutant by decreasing the stability of complex I. Furthermore, our results demonstrate that increase in complex I stability, improves mitochondrial function and decreases mitochondrial stress, putting it inside a "window" of mitochondrial dysfunction that allows lifespan prolongation.

Link: http://dx.doi.org/10.1371/journal.pone.0059493

Source:
http://www.fightaging.org/archives/2013/04/mitochondrial-functional-mutations-and-worm-longevity.php

The indy gene - named for "I'm not dead yet" - was one of the earliest longevity mutations to be uncovered in flies, and consequently is somewhat better studied than the many that have followed since then. Here is an open access paper on the subject:

Decreased expression of the fly and worm Indy genes extends longevity. The fly Indy gene and its mammalian homolog are transporters of Krebs cycle intermediates, with the highest rate of uptake for citrate. Cytosolic citrate has a role in energy regulation by affecting fatty acid synthesis and glycolysis. Fly, worm, and mice Indy gene homologs are predominantly expressed in places important for intermediary metabolism. Consequently, decreased expression of Indy in fly and worm, and the removal of mIndy in mice exhibit changes associated with calorie restriction, such as decreased levels of lipids, changes in carbohydrate metabolism and increased mitochondrial biogenesis. Here we report that several Indy alleles in a diverse array of genetic backgrounds confer increased longevity.

The paper is a good example of the way in which calorie restriction muddies the water of longevity studies; the effects of calorie restriction on life span are very strong in lower animals like flies and worms, and many past studies failed to fully account for differing dietary calorie intakes between populations of these animals. The authors of this paper point out a number of past papers with results that may tainted due to differing calorie intake, and note that their own work tries to control for this.

Link: http://www.frontiersin.org/Genetics_of_Aging/10.3389/fgene.2013.00047/full

Source:
http://www.fightaging.org/archives/2013/04/indy-mutations-and-fly-longevity.php

A range of research in laboratory animals associates alterations to the reproductive system with alterations in longevity. Nematode worms live longer if you remove their germ cells, for example. Transplanting younger ovaries into older mice extends life as well. There is some thought that these varied approaches work through common longevity mechanisms such as insulin-like signaling pathways, but that's by no means certain.

Here is another set of data to add to the existing research on this topic:

Reproduction is a risky affair; a lifespan cost of maintaining reproductive capability, and of reproduction itself, has been demonstrated in a wide range of animal species. However, little is understood about the mechanisms underlying this relationship. Most cost-of-reproduction studies simply ask how reproduction influences age at death, but are blind to the subjects' actual causes of death. Lifespan is a composite variable of myriad causes of death and it has not been clear whether the consequences of reproduction or of reproductive capability influence all causes of death equally.

To address this gap in understanding, we compared causes of death among over 40,000 sterilized and reproductively intact domestic dogs, Canis lupus familiaris. We found that sterilization was strongly associated with an increase in lifespan, and while it decreased risk of death from some causes, such as infectious disease, it actually increased risk of death from others, such as cancer.

Although a retrospective, epidemiological study such as this cannot prove causality, our results suggest that close scrutiny of specific causes of death, rather than lifespan alone, will greatly improve our understanding of the cumulative impact of reproductive capability on mortality. Our results strongly demonstrate the need to determine the physiologic consequences of sterilization that influence causes of death and lifespan. Shifting the focus from when death occurs to why death occurs could also help to explain contradictory findings from human studies.

Link: http://dx.doi.org/10.1371/journal.pone.0061082

Source:
http://www.fightaging.org/archives/2013/04/sterilized-dogs-live-longer.php