Appendices: Two Unusual Potential Sources of Funding for Longevity Research Editorial Note The following appendices (A and B) provide information that may be useful to investigators seeking funding for experimental types of aging intervention that may be difficult to fund through more traditional sources. The Editors make no represen- tations about the ability of the presenting organizations to fund research or about the veracity of the presenting organizations’ views about the biology of aging or of the prospects for intervening into aging in the ways envisioned by either of these orga- nizations. Our intention here is simply to inform readers about additional possible sources of support for their research. – The Editors G.M. Fahy et al. (eds.), The Future of Aging, DOI 10.1007/978-90-481-3999-6, 807 C Springer Science+Business Media B.V. 2010 Appendix A SENS Foundation: Accelerating Progress Toward Biomedical Rejuvenation Michael Rae A.1 Invitation to Submit Research Proposals SENS Foundation (website: http://www.sens.org/) is positioned as the most effective philanthropic organization investing in biomedical gerontological research today: a California-based biomedical nonprofit1 committed to critical-path research within a comprehensive panel of therapeutics that is aimed at curing age-related disease, disability, suffering, and death. This mission most obviously distinguishes the Foundation from the large number of nonprofit organizations devoted to treatments for specific age-related diseases. However, the Foundation’s unique strategic approach to advancing progress toward the cure of biological aging is also unique even within the small field of organi- zations devoted to biogerontological research. The Foundation’s focus is on the development of biomedical interventions rather than on descriptive studies – and on interventions that will not simply retard the rate of aging, but restore the aged body’s original biomolecular- and cellular-level fidelity – and through it, replace the frailty of biological age with the robust homeostatic resilience of biological youth. To this end, SENS Foundation directly funds research projects aimed at the ulti- mate development of interventions to remove, repair, replace, or render harmless molecular and cellular damage prevalent in the body in situ late in life. We are now inviting all qualified researchers in the biological or medical sciences to submit proposals aimed at molecular- and cellular-level structural ‘rejuvenation’ of the aging body. Established fundable program areas and Requests for Proposals (RFPs) for specific projects are outlined below. M. Rae (B) SENS Foundation, 1230 Bordeaux Drive, Sunnyvale, CA 94089, USA e-mail: [email protected] 1SENS Foundation is a California nonprofit organization, and is in the process of applying for recognition of exemption from taxation under section 501(c)(3) of the Internal Revenue Code. The organization expects to receive tax-exempt status effective as of the date of incorporation. 809 810 M. Rae A.2 Funding Priorities and Principles SENS Foundation’s research funding priorities emerge from critical-path analy- sis of areas of high biomedical importance within the “Strategies for Engineered Negligible Senescence” (SENS) platform proposed by Dr. Aubrey de Grey to develop a comprehensive panel of robust anti-aging interventions. As explained in detail elsewhere (de Grey 2003; de Grey et al. 2002; de Grey and Rae, 2007), SENS is based on an “engineering” heuristic for the development of therapeutics targeting biological aging, in contrast to the so-called “gerontological” approach that underlies most past and present attempts to do so. SENS Foundation is the only nonprofit organization whose research funding is devoted to biomedical gerontology, but whose remit allows it to avoid the diversion of funds into the inefficient “gerontological” approach. Instead, SENS Foundation’s research program targets funding to research that advances the development of the specific biotechnologies identified through the “engineering” approach to anti-aging biomedicine: in essence, the extension of regenerative medicine principles to aging. I will now outline these two approaches, and the reasons why the Foundation’s strategy of targeted investments in the former rather than the latter can be expected to yield anti-aging interventions of dramatically greater benefit. A.2.1 The “Gerontological” Approach: Modulation of Metabolic Pathways Contributing to Biological Aging There is broad-based consensus in biogerontology (e.g., Kirkwood, 2008; Hayflick, 2007; Holliday, 2004; de Grey et al. 2002) that aging is the result of accumulat- ing stochastic damage to the body’s cellular and molecular structures, as a result of unintended biochemical side-effects of metabolism such as reactive oxygen species (ROS), nonenzymatic glycation, and errors in DNA replication and epigenetics. Most biogerontology research, therefore, is based on enhancing our understanding of those metabolic processes and their mechanistic links to aging damage, in hopes that those pathways can be modulated in ways that reduce the rate at which such damage forms and accumulates, leading in turn to a slower loss of physiological integrity and retarded organismal aging. Within this framework, putative interventions might downregulate pathways responsible for ROS generation, sequester reactive intermediates of glycolysis, upregulate repair mechanisms, interfere in the action of anabolic pathways respon- sible for cellular proliferation, or otherwise antagonize or cushion such pathways. Examples will come readily to mind, and pervade the choice of interventions selected for inclusion in the NIA’s Interventions Testing Program (ITP (Nadon et al. 2008; National Institute on Aging 2008). This way of pursuing anti-aging intervention is grounded in the logic of basic research science: analyze a phenomenon in progressively finer detail to discover its underlying basis, and then use the results of such studies to modify hypotheses, thereby generating new questions in a recursive process of scientific progress. Appendix A: SENS Foundation 811 The same strategy is also widely employed as part of conventional drug devel- opment. Researchers begin by analyzing and characterizing the various components of a metabolic pathway that is defective in the disease state, identifying the normal function of each. They then compare the function of those components in health and disease, thereby revealing the dysfunctional steps in the process that form the molecular basis of the illness. Such components then become therapeutic targets, subject to manipulation to normalize function, whether by small molecules or other means (such as gene therapy or prosthesis). Unfortunately, this strategy is ill-suited to the near-term development of inter- ventions against the biological aging process, for the overarching reason that aging damage is not the result of the de novo dysfunction of metabolic pathways, but of the undesirable biochemical side-reactions of normal metabolic activity.This is precisely why aging is a universal disease, and why many physicians and even biogerontologists are reluctant to characterize it as a “disease” at all: biological aging is the pathological result of perfectly-functioning, “healthy” – but necessarily imperfect – metabolic processes. Hence Dr. de Grey’s quip that “aging is a side- effect of being alive.” In other words, any “gerontological” anti-aging intervention would of necessity be grounded upon interfering with the biochemical processes that sustain our very lives – and doing so day in and day out, from the day that a “patient” first begins therapy until his or her death. The pathways whose reactive products contribute to aging are there for a rea- son, even though they have long-term downsides, and we begin dialing them up or down at our peril. Even the reactive products that link metabolism to aging dam- age are often indispensable, evolution having learned to harness them for metabolic purposes, such as when ROS are used as signaling molecules (DAutréaux and Toledano, 2007). Indeed, the body’s metabolic processes are already embedded within hopelessly complex regulatory pathways and interlocking feedback loops, precisely in order to ensure that they continue to operate in strict coordination with one another, and within a range that natural selection has ‘learned’ to be optimal for sustaining fitness. This fact is illustrated in the very phenomena that advocates of “gerontological” intervention seek to mimic pharmacologically: animals that age slowly because of either genetic mutations or the imposition of calorie restriction. Slow-aging organ- isms are vanishingly rare in natural populations for a reason: not that evolution “wants us to age” as is often mistakenly said, but because the metabolic abnormal- ities that are responsible for such animals’ slow-aging phenotype also ensure that they can only survive in the sheltered conditions of the laboratory. In the wild, these organisms would be unfit relative to their normally-aging cohorts for most of their natural lifespans, and the more aggressively the interventions are applied to enhance the anti-aging effect, the more severe the phenotype would become. An additional, and equally crucial, limitation to “gerontological” intervention is that no matter how much the accumulation of further aging damage is slowed by such means, it cannot be entirely stopped without turning off the underlying metabolic processes entirely. Nor can such interventions