This article explores some of the regulatory challenges facing those who would bring rejuvenation biotechnologies, like those pursued by Dr. Aubrey de Grey and the SENS Foundation, to market. It does not presume familiarity with Dr. de Grey and his work; I’ve tried to make it informative to all alike.

The Conquest of Aging

Biomedical gerontologist Aubrey de Grey predicts that the first human being to live to 1,000 years old is alive today. Who exactly that person might be – or rather, how old they are today – is a detail that Dr. de Grey has wavered on, but he has remained firm in his commitment to that prediction, and is certainly one of the most prominent figures working towards realization of the technologies required to make his prophecy reality. In his book, Ending Aging, Dr. de Grey describes his proposed approach to the “problem” of aging, and how it differs from those presently in practice.[1]

In Dr. de Grey’s opinion, the current paradigm devotes a vast majority of resources to geriatric care, which attempts to cure or manage age-associated diseases only after they emerge as recognizable groupings of symptoms. To quote an apt metaphor from another longevity advocate:

“[T]he challenge of treating illnesses in the elderly must at times seem like Heracles’ trials of combating the multi-headed Hydra. Each time one head was severed, two more would sprout in its place. Likewise, a patient might survive a serious cardiac episode with help of antihypertensive drugs only to succumb to cancer and dementia.”[2] [emphasis in original]

Meanwhile, the (significantly smaller) remaining portion of research dollars goes towards biogerontology, which studies the upstream causes of aging, any benefit of which is probably unrealizable for several human generations. However, Dr. de Grey argues that without necessarily knowing much more about the upstream causes of aging than is currently understood, it is already possible to categorize the different forms of aging “damage,” and devise therapies that will repair the damage at a sufficient rate to achieve what he terms “longevity escape velocity.”

Dr. de Grey calls his theory “Strategies for Engineered Negligible Senescence” (SENS). There are seven strategies, each related to one of the seven major categories of aging damage thus far discovered. Those categories (and proposed therapies) are: (1) cancer-causing nuclear mutations (removal of telomere-lengthening machinery, aka OncoSENS); (2) mitochondrial mutations (allotopic expression of 13 proteins, aka MitoSENS); (3) intracellular junk (novel lysosomal hydrolases, aka LysoSENS); (4) extracellular junk (immunotherapeutic clearance, aka AmyloSENS); (5) cell loss & tissue atrophy (stem cells and tissue engineering, aka RepleniSENS); (6) cell senescence (targeted ablation, aka ApoptoSENS); and (7) extracellular crosslinks (AGE-breaking molecules and tissue engineering, aka GlycoSENS). The SENS Foundation was established in 2009, helped in part through seed funding provided by Peter Thiel, co-founder of PayPal and a managing partner of The Founders Fund. The SENS Foundation’s stated purpose is “to research, develop and promote comprehensive regenerative medicine solutions for the diseases and disabilities of aging.”[3]

Delving into the details of each of Dr. de Grey’s proposed strategies is beyond the scope of this article, but it is worth taking a closer look at one of the seven. LysoSENS aims at “junk” molecules which cannot be broken down by human lysosomal enzymes. Over time, these molecules accumulate within cells, contributing to conditions like macular degeneration, atherosclerosis, and Alzheimer’s disease (AD)[4]. Dr. de Grey’s proposition is to search for novel lysosomal enzymes (novel to humans, that is) in bacteria, molds, and other microbes that are involved in “recycling” dead animal bodies, since the “junk” inside our cells is — along with the  rest of us — food to them. SENS research being carried out at Rice University has already identified one such enzyme that, when targeted to the lysosome, decreases cytotoxicity of 7-ketocholesterol (7KC), an oxysterol associated with atherosclerosis and Alzheimer’s disease.[5] Enzyme replacement therapy is already used for the treatment of lysosomal storage diseases not associated with aging, like Gaucher’s disease. Insofar as it could be used to treat a condition (or conditions) remedially, a therapy targeting 7KC with a novel lysosomal enzyme might otherwise resemble traditional approaches to disease treatment, but it could also be used preventively. Other SENS pose even greater challenges to the traditional distinctions between cure, prevention and enhancement. The objective of MitoSENS, for instance, is to render the recipient immune to the fallout consequences of mitochondrial DNA mutations by placing backup copies of the thirteen mitochondrial genes — which naturally reside only inside the mitochondria — into the cell nuclei. Significant research progress is being made into this strategy as well.[6]

The problem of normative definitions of aging

Dowsing for fountains of youth is well and good, but won’t get us very far unless they can be tapped and piped to the marketplace, and while there are many scientific obstacles to overcome before rejuvenation biotechnologies are realized, there are also social, political and legal ones. Many of these problems are definitional. For one, what exactly distinguishes age-associated diseases and conditions from “normal” features of aging? In the words of one scholar: “[F]rom the perspective of modern biogerontology, there is little to distinguish biological ageing from a disease state…. To argue that ageing is not a disease by virtue of its universality is as misleading as it is to argue that the Basenji is not a dog because it does not bark.”[7] But to dismiss this debate as purely semantic or philosophical would be to misunderstand the true difficulty the definitional problem poses.

The U.S. Food, Drug and Cosmetic Act defines “drug” as, inter alia, “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals.” [8] So far so good, because even if the U.S. Food and Drug Administration (“FDA”) did not agree that a particular undesired physical state was a “disease” for the purposes of the first definition, it would be difficult to deny that a proposed therapeutic (whether a chemical entity or a biological product[9]) was not intended to affect the structure or functioning of the body, at some level. However, present regulatory approval pathways indirectly require that a drug be “indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition.”[10] [emphasis mine]. The phrase “recognized disease or condition” is not defined in this context[11], and the FDA is not itself the recognizer, but rather looks for consensus within the clinical and/or scientific communities regarding the existence of a particular disease or condition, and of clear criteria for clinical diagnosis thereof.[12] To quote one author: “To the extent that many problems of ageing have not been formally recognized by any of these processes, the FDA has no clear guidance on how to determine if a proposed indication would be acceptable.” [13]

For many age-associated conditions, the question of “recognition” is a valueladen debate. While some commentators will no doubt accuse longevity advocates of “disease-mongering”[14], Dr. de Grey would probably argue that that sort of reaction is a symptom of what he terms the “pro-aging trance”[15] — a terror management strategy that accepts and embraces the apparently unavoidable progressive wasting of one’s body (and mind), instead of rejecting and resisting it. But the cognitively dissonant distinction between normal, “healthy” aging on the one hand, and “diseases” of aging on the other is not impermeable. For some historical perspective, it is worth considering the example of Alzheimer’s disease. When it was first described in 1910, AD only included what is now referred to as “earlyonset Alzheimer’s disease,” i.e., when the symptoms of “senile dementia” appeared in someone under 65.[16] Due to its vastly less frequent incidence, this “presenile dementia” was assumed to be distinct from the normal variety. However this normal/ abnormal categorization broke down in 1977, due to professional recognition of their near identical symptomologies, making the early-onset subtype by far the minority of AD incidence.[17]

A present-day example of this process of recognizing “normal” features of aging as diseases or conditions of aging, is the case of sarcopenia. Sarcopenia (literally “poverty of the flesh”) describes the degeneration of skeletal muscle mass and strength that occurs with aging that contributes (in part) to disability, frailty, and morbidity in older persons.[18] Until fairly recently, sarcopenia and related conditions like sarcopenic obesity were considered “normal” aspects of aging, much like senile dementia prior to 1977. To be fair, both sarcopenia and senile dementia are normal, insofar as they are common conditions in older persons — but that does not mean they are untreatable, nor that they should be left untreated. A number of potential drug targets have been identified that may be of use in treating sarcopenia[19], but if consensus recognition of the condition is lacking there may not yet be a regulatory pathway for licensing therapeutics to treat it.[20]

Thus, as it stands, forging a regulatory pathway for treatments of a common, disabling (and in some cases indirectly lethal) feature of aging involves two distinct steps: first, persuade the scientific and clinical communities that a particular symptomology of aging can and should be treated, and second, persuade the FDA that everyone else is persuaded. But this is not insurmountable. The European Working Group on Sarcopenia in Older People published a “practical clinical definition and consensus diagnostic criteria for agerelated sarcopenia” in 2010[21], which was followed by a consensus definition from The International Working Group on Sarcopenia in 2011[22]. In the U.S., the Foundation for the National Institutes of Health, the National Institute on Aging, and the FDA held a Sarcopenia Consensus Summit on May 8-11, 2012.[23] A number of clinically meaningful end points have been proposed for assessing treatment efficacy[24], including patient-reported outcomes.[25] Under appropriate regulatory supervision, medicalization of sarcopenia would help older persons maintain or even regain functional independence and quality of life — and perhaps boost lifespan, via a reduction in comorbidity with diseases like osteoporosis.

The problem of causally interrelated disease states

There is another definitional problem: What distinguishes one age-associated disease from another? This may seem like a facetious question, given the obvious symptomatic differences between atherosclerosis and AD. However, as mentioned above, the oxysterol 7KC has been implicated in the pathogenesis of both those disease states. If 7KC is indeed a metabolic byproduct that is causally related to both atherosclerosis and AD then, in addition to being a promising drug target itself, it could conceivably qualify as a surrogate endpoint for clinical trials of new drugs indicated for those diseases. FDA has issued a draft guidance regarding qualification of biomarkers as drug development tools[26], but surrogate endpoints may only be used in lieu of direct measures of clinical benefit under the FDA’s “Fast-Track Program,” which is only available for new drugs intended for the treatment of a serious or lifethreatening condition and that demonstrate the potential to address unmet medical needs for such a condition.[27] However, it would not be necessary to qualify 7KC reduction as a surrogate endpoint for both AD and atherosclerosis. Doing so for one or the other based on which is thought to be the more serious condition and/or the greater unmet need would allow its use in a fast-tracked New Drug Application for the one indication, and then if safety and efficacy in humans is established and the therapeutic is approved, data from (likely compulsory) post-marketing studies could be used in a new indication claim for the other condition.

Surrogate endpoints need only be “reasonably likely to predict clinical benefit”[28], and some commentators have pointed out that applying this lower standard to the screening of surrogate endpoints may result in drugs approved on the basis of evidence of an effect on a biomarker which, while related to the disease, is not actually causally related to any clinical benefit.[29] Of course, given its ambitious objective, the SENS Foundation has a strong vested interest in tying 7KC to clinical benefit, and the fact that FDA-qualified biomarkers are released into the public domain also fits within the Foundation’s public interest mandate, and could enhance perceptions of the legitimacy of its research goals. But more importantly, it could shorten clinical trials, an oft-criticized source of delay and drug costs. While its work to date has primarily been proof-of-concept research, in the future the SENS Foundation might devote some of its resources to running forms of aging damage like 7KC through the biomarker qualification process. Although publishing both the proof-of-concept and such valuable drug development tools might cut out some of the traditional patenting opportunities[30], it also offsets costs ordinarily borne by pharmaceutical companies. A little low-hanging fruit might stir up some productive competition in an industry sometimes criticized for chasing after minor therapeutic improvements and patent trolling.

Another option that is very in line with the social agenda of longevity advocates would be to promote the rebranding of multiple disease states with significantly overlapping low-level chemistry as single unified conditions that present varied symptom groupings based on exposure to particular environmental factors (including the endogenous “environment,” like certain genes or epigenetic variations, along with more traditional exogenous contributors like diet, exercise, etc). Admittedly, this would be the more difficult path, because it relies on the two-step process of disease recognition, discussed above, and considering how long it took AD and senile dementia to be folded into AD with an early-onset subtype, trying to replicate this process with diseases that present as differently as atherosclerosis and AD may be a Sisyphean task. On the other hand, academic pressure of this kind could have trickle-out effects on the public, re-situating the discourse of age-associated diseases further upstream, pressing on towards greater recognition of aging as disease.

Finally, slight augmentations to the SENS branding could be in order. Dr. de Grey gave unique names to his proposed strategies (LysoSENS, MitoSENS, etc.), but not to the categories of damage which are the targets of those strategies. Devising and promoting novel medical names for these categories of damage, like idiocytotoxicosis[31] for the “intracellular junk” targeted by LysoSENS, might prompt frame-shifting in the academic and clinical communities that could consequently (albeit indirectly, and thus probably slowly) broaden the scope of “recognized disease or condition”. Sadly for the planet, ‘junk’ doesn’t seem to be something humans take terribly seriously — idiocytotoxicosis, on the other hand, well that’s clearly a monster. Perhaps this suggestion borders on “disease-mongering” — but isn’t that term itself equally agenda-driven, given the not-so-subtle association with war-mongering? Dr. de Grey and other longevity advocates consider themselves to be on moral high ground, so these kinds of accusations are only of consequence if they provoke counter-productive public response, and reframing well-recognized diseases like AD and atherosclerosis as symptoms of underlying “metabolic pathology” can hardly be characterized as “questionable new diagnoses — like [premenstrual dysphoric dysfunction] and social anxiety disorder — which are hard to distinguish from normal life,” the likes of which give at least one critic concern. [32] And perhaps it is the very idea that “normal” is the ultimate objective — as opposed to simply “better” — that is the problem.

What’s the alternative?

If the perceived burden is too high, and the cost of doing nothing too great, stakeholders may look to circumvent the FDA. The SENS Foundation characterizes the assault on aging as the next space race.If the U.S. doesn’t take action to foster local development of what will assuredly be highly sought-after therapies, the movement may simply move underground (i.e. further in the vein of DIYbio), and overseas (medical tourism, and seasteads), which will only hamper the FDA’s mandate to protect Americans from harm.

Endnotes

[1]: Aubrey de Grey & Michael Rae, Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime, (New York: St Martin’s Press, 2007).

[2]: David Gems, “Tragedy and delight: the ethics of decelerated aging” (2011) 366 Philosophical Transactions of the Royal Society B [Phil Trans R Soc B] 108 at 110.

[3]: SENS Foundation, SENS Foundation, online: <http://www.sens.org/about-thefoundation>.

[4]: Jacques M Mathieu et al, “7-Ketocholesterol Catabolism by Rhodococcus jostii RHA1” (2010) 76:1 Applied and Environmental Microbiology 352.

5]: Jacques M Mathieu et al, “Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase” (2012) Biotechnology and Bioengineering, online:
<http://www.wileyonlinelibrary.com> DOI 10.1002/bit.24506.

[6]: SENS Foundation, Research Report 2011, online: <http://images.sens.org/reports/ SENS%20Research%20Report%202011.pdf>.

[7]: Supra note 2 at 109.

[8]: 21 USC § 321(g)(1).

[9]: 42 USC § 262(i). The phrase “analogous product” has been used to justify the extension of the FDA’s regulatory authority to human cells, tissues, and cellular and tissue-based products (HCT/Ps). See also Areta L Kupchyk, “Approval of Products for Human Use” in HB Wellons et al, Biotechnology and the Law (ABA, 2007) 591 at 617, note 41

[10]: 21 CFR § 201.57(c)(2) Specifically, this is a labeling requirement, but if a drug cannot be labeled according to the regulation, the New Drug Application cannot be approved. See also 21 CFR § 201.56.

[11]: The term disease is defined in 21 CFR §101.93(g) for the purposes of disease claims relating to dietary supplements, but that is only applicable in that context. See also 21 USC 343(r)(6).

[12]: William J Evans, “Drug discovery and development for ageing: opportunities and challenges” (2011) 366 Phil Trans R Soc B 113 at 114.

[13]: Ibid at 114.

[14]: Barbara Mintzes, “Disease Mongering in Drug Promotion: Do Governments Have a Regulatory Role?” (2006) 3:4 PLoS Medicine e198.

[15]: Aubrey de Grey, “Combating the Tihtonus Error: What Works?” (2008), 11:4 Rejuvenation Research 713.

[16]: GE Berrios, “Alzheimer’s disease: a conceptual history” (1990) 5:6 International Journal of Geriatric Psychiatry 355.

[17]: Robert Katzman et al, Alzheimer’s disease: senile dementia and related disorders (NY: Raven Press, 1978) at 595.

[18]: Eric P Brass & Kathy E Sietsema, “Considerations in the Development of Drugs to Treat Sarcopenia” (2011) 59:3 Journal of the American Geriatrics Society 530.

[19]: Ibid at 531.

[20]: Supra note 12 at 116.

[21]: Alfonso J Cruz-Jentoft et al, “Sarcopenia: European consensus on definition and diagnosis” (2010) 39:4 Age and Ageing 412 (Abstract).

[22]: Roger A Fielding et al, “Sarcopenia: An Undiagnosed Condition in Older Adults. Current Consensus Definition: Prevalence, Etiology, and Consequences” (2011)12:4 Journal of the American Medical Doctors Association [JAMDA] 249 (Abstract).

[23]: See Marco Brotto, “Lessons from the FNIH-NIA-FDA sarcopenia consensus summit” (2012) 9 IBMS BoneKEy 210.

[24]: Supra note 18 at 531-533.

[25]: Ibid at 533. See also Christopher J Evans et al, “Development of a New Patient-Reported Outcome Measure in Sarcopenia” (2011) 12:3 JAMDA 226.

[26]: Center for Drug Evaluation and Research, “Guidance for Industry – Qualification Process for Drug Development Tools,” FDA (October 2010) online: <http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM230597.pdf>.

[27]: 21 USC § 356(a)(1).

[28]: 21 CFR § 314.510.

[29]: Thomas R Fleming, “Surrogate Endpoints And FDA’s Accelerated Approval Process” (2005) 24:1 Health Affairs 67. See also Thomas R Fleming and David L DeMets, “Surrogate end points in clinical trials: are we being misled?” (1996) 125:7 Annals of Internal Medicine 605.

[30]: There may be other intellectual property issues implicated in this shift of paradigm in drug development and regulation, but they are beyond the scope of this article.

[31]: Meaning “self, one’s own” + “cell” + “toxin” + “condition of increase”.

[32]: Supra note 14 at 0463.

[33]: SENS Foundation, Annual Report 2011, online: <http://www.sens.org/sites/ srf.org/files/SENS%20Foundation%20 Annual%20Report%202011.pdf>.

First published as a regular column called In Perpetuity in Cryonics Magazine, March 2013