16. September 2016 · Comments Off on The Multi-Headed Hydra · Categories: Science, Society

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

08. August 2016 · Comments Off on How Uniform Are The Uniform Anatomical Gift Acts? · Categories: Cryonics, Society

“SECTION 11. PERSONS THAT MAY RECEIVE ANATOMICAL GIFT; PURPOSE OF ANATOMICAL GIFT”

Thus begins a very important section of a very important piece of legislation. Except it isn’t actually legislation at all, though it does look the part. It is the Revised Uniform Anatomical Gift Act (2006) [“UAGA”]. UAGA is model legislation, and in that form it does not have the force of law.

The model act continues:

(a) An anatomical gift may be made to the following persons named in the document of gift:

(1) a hospital; accredited medical school, dental school, college or university; organ procurement organization; or other appropriate person, for research or education;

Crucially, this section tells us under what, if any, authority we may direct that a cryonics service provider take custody of our bodies after legal death. Whether on plain meaning, or act-specific definition, cryonics service providers are not hospitals, medical or dental schools, colleges or universities. In some circumstances, Alcor and/or Suspended Animation behave like organ procurement organizations — insofar as brains are organs — but that term is defined in UAGA so as to require designation by the Secretary of the US Department of Health and Human Services. Subsection 2 (not reproduced above) is specific to organ transplantation, and subsection 3 pertains to eye banks and tissue banks, neither of which are good “homes” for a cryonics service provider.

So, for the time being we are left with “or other appropriate person, for research or education.” It isn’t much — but it’s home, and on that point at least one court agrees, namely the Court of Appeals of Iowa in Alcor Life Extension Foundation v Richardson. [1] But wait — how does a court in Iowa even begin to consider the meaning and effect of UAGA if it isn’t really law? Well, because the Iowa Legislature looked at the model uniform act, decided it liked it (mostly), and made it into state law. In fact, the Iowa Legislature made some changes to the model, but it left in the “other appropriate person” clause, and that is very good, because when Alcor sued Orville Richardson’s brother and sister for custody of Orville’s body, the Court of Appeals of Iowa agreed that Alcor was an “appropriate person for research” for the purposes of Iowa’s UAGA. [2]

Thus, we can see how important these words are. As the name implies, UAGA is an attempt to promote uniformity in an area of law which could otherwise vary considerably from state to state, making the procurement and transfer of life-saving organs and other tissues for transplant very difficult. So the Uniform Law Commission [3] came along and drafted UAGA for enactment in all states. Of course, this process is voluntary on the part of the states, and does not require wholesale adoption of the model act without modification — and that is where potential for trouble creeps in. Human cryopreservation is obviously not the intended subject of the act; even generally, gifts for research and education are only a secondary focus. In most states (Arizona being a conspicuous exception) there is no cryonics lobbyist at the table when state legislators are deliberating whether and how to enact the newest incarnation of UAGA; hence, they are not thinking about us or our unique interests when they consider whether to pass the model act with the words “or other appropriate person, for research or education” intact.

Now, section 24 of UAGA does state that “[i]n applying and construing this uniform act, consideration must be given to the need to promote uniformity of the law with respect to its subject matter among states that enact it.” But of course, the force of that section depends on whether or not it was itself legislated with the rest of the Act. However, assuming it was, this provision still cannot outweigh clear evidence of a legislature’s intent to diverge from the model by removing or materially altering particular language. That is to say, if the “other appropriate person” clause is left out of one state’s enactment of UAGA, a court has no discretion to read it in. [4] Where the uniformity provision does help is if Alcor ever has to go to court again in a state with a UAGA substantially similar to Iowa’s — then the Iowa case should carry significant persuasive force. [5] Happily, a majority of states’ UAGAs contain the “other appropriate person” clause, unaltered. [6] A few others have adopted different language that is equally or maybe even more applicable to cryonics organizations [7], and two states may even provide additional points of entry for cryonics service providers. [8] However, nine states present problematic aberrations from the mold. In Oklahoma, the State Anatomical Board gets to designate who is an “other appropriate person.” [9] Likewise, the Virginia Transplant Council is in charge of authorizing “other appropriate persons” in Virginia [10], and in the District of Columbia this is the domain of the mayor. [11] The remaining six states lack the “other appropriate person” clause entirely, and any other equivalent entry point: these are California, Florida, Maryland, New York, Texas, and Washington. [12] It is a little surprising to see some current (and in Texas’ case, future [13]) hubs of cryonics activity on this list.

At this stage, I feel I should point out that anatomical gift legislation is only one mechanism for making legal provisions for transference of custody of one’s body after legal death. The other (arguably more traditional) method is the “final disposition of human remains” method. Thus, the mere fact that a state’s anatomical gift legislation does not permit donations to cryonics organizations doesn’t rule out  legally enforceable cryonics arrangements. The nine states mentioned above all have some statutory provision for the disposition of human remains route, though Florida stands out for lack of clarity. Maryland and Oklahoma both provide the right to direct the disposition of one’s body after death. [14] Written preferences are likewise binding in California, District of Columbia, New York, Texas, and Washington, which states also provide the right to designate a person who will supersede the spouse or next of kin’s default authority to control disposition (though they would be bound by the decedent’s written instructions in any case). [15] Virginia allows for designation in writing of a person who will control disposition (over a surviving spouse or other next of kin), but the relevant statute does not expressly state that the decedent’s instructions are binding — though it could be argued that it is implied.[16] Florida’s statutes are not explicit as to who controls the disposition of human remains after death, nor whether written preferences of the deceased are legally binding, though case law has generally supported this result. [17]

However, even if the nine states whose anatomical gift statutes apparently preclude donation to cryonics organizations still provide legally enforceable final disposition rights, mightn’t a document that uses language around “anatomical donations” for this second purpose present somewhat of a red herring? For example, Alcor’s success in the Richardson case relied in part on the fact that Iowa’s UAGA takes precedence over its final disposition provisions, which would have favoured Orville’s brother and sister to control disposition. [18] But when an anatomical gift under UAGA fails for lack of a valid donee, the gift doesn’t fail, but passes instead “to the appropriate procurement organization” (which would not include the cryonics service provider).[19] Would this aspect of UAGA prevail over the cryonicist’s clear intent, just because he or she used the words “anatomical donation”? This result seems inconceivably formalistic, but illustrates the (potential) problem with blending legal categories. On the other hand, because we cannot necessarily control which anatomical gift legislation will ultimately apply to us (as it will be the law of whichever jurisdiction we die in, whenever that happens to be), a hybrid, one-size-fits-most solution has clear utility.

As a Canadian, my interest in UAGA was actually initially focused north of the border. I noticed that Cryonics Institute’s standard issue emergency necklace has “UNIFORM ANATOMICAL GIFT ACT” on the back, and I wondered what Canadian medical personnel might make of that, since we have no such named legislation. However, the intent of CI’s “Uniform Donor Form” [20] is fairly clear, and the majority of Canadian provinces have broadly empowering legislation for making “human tissue gifts.” [21] This is especially good because English-Canadian common law never developed the deferential approach taken by US judges to decedents’ preferences for final disposition — such preferences were only ever considered morally binding on executors and next of kin, and not legally so. [22] However, Alberta’s Human Tissue and Organ Donation Act only permits body donations to university medical, dental or related health programs. [23] This limitation expressly refers to “a body donated under this Act” as opposed to “any tissue, organ or body donated under this Act,” so it could be argued that Alcor neuropatients may still be transferred using the anatomical gift mechanism — but this may not reflect the intent of legislature, and as such may not be a sustainable reading. Unfortunately, this would mean that Albertans (or at minimum, Albertan whole-body patients) are hit doubly — they have no legally binding mechanism for transfer of custody of their bodies to their cryonics organization under either the anatomical gift or final disposition route.

So, more than most, Albertan cryonicists might want to reconsider the wisdom of where they live. That said, while other readers may think themselves lucky to live in a state or province I didn’t mention, laws change [24], and I have just learned all-too-personally how many fifty states are to monitor. We must each be vigilant in ensuring our various cryonics legal documents are valid for their intended purposes.

Endnotes:

1 785 NW (2d) 717 (Ill Ct App 2010).

2 Ibid at 725.

3 http://www.uniformlaws.org

4 UAGA’s choice of law provision (section 19) states that a document of anatomical gift will be valid if it is executed in accordance with either (i) the law of the forum (i.e. the UAGA where the document is sought to be used), (ii) the law of the state/country where it was executed, or (iii) the law of the state/country where the person was domiciled, had a place of residence or was a national when the document was executed. However, the interpretation of the document of gift is governed by the forum law.That is to say, a document of anatomical gift to a cryonics service provider which is formally valid in the forum by merit of its validity under the laws of the state/country where it was executed, etc., may yet be ineffective under the laws of the forum.

5 The Richardson decision also included a tentative, but nonetheless authoritative finding that Orville’s payment to Alcor to preserve his body, and less-than-perfectly-altruistic motives did not move the transaction outside the legal category of “gift.”  Again, this finding and the uniformity provision should go a long way to deciding the issue if it comes up again in another state.

6 For ease of reference: Alabama, Alaska, Arkansas, Arizona, Connecticut, Georgia, Hawaii, Idaho, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Massachusetts, Michigan, Mississippi, Missouri, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, North Carolina, North Dakota, Ohio, Oregon, Rhode Island, South Carolina, South Dakota, Tennessee, Utah, Vermont, West Virginia, Wisconsin, Wyoming.

7 Minnesota replaces “other appropriate person” with “non-profit organization in medical education or research.” Minn Stat § 525A.10. Delaware, Illinois, and Pennsylvania still use language from older incarnations of the UAGA, which lack “other appropriate person” but define “any bank or storage facility” in such a way that so long as the cryonics service provider is recognized as a permissible donee in its home state, it should qualify under the Delaware/Illinois/Pennsylvania statutes. 16 Del Code § 2712, 755 ILCS § 50/5-10, 20 Pa C S § 8612.

8 Alcor’s own lobbying efforts resulted in the inclusion of the comparatively broadly defined “procurement organization” in Arizona’s ARS §36-850; Missouri has provision for “cadaver procurement organization[s]”. Mo Rev Stat § 194.255.

9 63 OS §2200.11A.

10 Va Code § 32.1-291.11

11 DC Code §7-1531.10.

12 Cal Health & Safety Code § 7150.50; Fla Stat § 765.513; Md Code, Est & T §4-509; NY PBH Law §4302; Texas Health & Safety Code § 692A.011; RCW § 68.64.100.

13 Comfort, Texas is home to the Timeship project.

14 Md Code, Health §5-509; 21 OS § 1151.

15 Cal Health & Safety Code §7100.1; DC Code §3-413; NY PBH Law §4201.2(c); Texas Health & Safety Code § 711.002; RCW § 68.50.160.

16 Va Code §54.1-2825.

17 Fla Stat § 497.005(37) sets out an apparent order of priority in a definitions section, without elsewhere stating that that priority grants any particular rights; § 732.804 uses permissive language instead of imperative. See also Leadingham v. Wallace, 691 So (2d) 1162 (Fla 5th DCA 1997).

18 Supra note 1 at 727.

19 Uniform Anatomical Gift Act (2006), § 11(c)(4).

20 http://www.cryonics.org/documents/Uniform. html

21 These are largely derived from various iterations of the Uniform Human Tissue Gift Act proposed by the Uniform Law Conference of Canada.

22 Quebec and British Columbia are the only provinces which provide statutory rights to direct disposition of one’s own human remains: art 42 CCQ and Human Tissue Gift Act, RSBC 1996 c 211 s 4.

23 SA 2006 c H-14.5 s 3.

24 For example, the 2006 revision of UAGA was introduced in the Pennsylvania Legislature this year.

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

01. July 2016 · Comments Off on Advances in Cryoprotectant Toxicity Research · Categories: Cryonics, Science

There is little disagreement among cryobiologists that the biggest limiting factor to reversible organ cryopreservation is cryoprotectant toxicity. It is actually not that hard to create vitrification solutions that completely inhibit ice formation at even the slowest cooling rates. The problem is that such highly concentrated vitrification solutions are too toxic to permit recovery of complex tissues. The least toxic vitrification solution for complex mammalian organs as of writing is M22. M22 is the culmination of many years of experimental and theoretical work by cryobiologist Greg Fahy and colleagues using rabbit kidney slices. Studying selected cryoprotectant mixtures on rabbit kidney slices, Fahy and colleagues came to the following conclusions:

1. High concentrations of a cryoprotective agent (or a mixture of different cryoprotective agents) can prevent ice formation during cooldown and warming.

2. The toxicity of some cryoprotectants can be neutralized by combining them with other cryoprotective agents.

3. The non-specific toxicity of a  cryoprotectant solution can be predicted by calculating a quantity (“qv*”) which is intended to measure the average hydrogen-bonding strength of the cryoprotectant polar groups with the water molecules in the solution.

4. Within limits, non-penetrating agents can reduce the exposure of cells to toxic amounts of cryoprotectants without reducing vitrification ability.

5. Synthetic “ice blockers” can be included in a vitrification mixture to reduce the concentration of toxic cryoprotective agents necessary to achieve vitrification.

While M22 is a low toxicity solution, its toxicity profile still necessitates minimizing exposure time and introduction and removal at low (subzero) temperatures. If we had a better understanding of the mechanisms of cryoprotectant toxicity, vitrification solutions with no toxicity at all could be introduced at higher temperatures and exposure times could be increased to optimize complete equilibration of the tissue with the cryoprotectant. It would also allow safer storage at intermediate temperature temperatures (around -130 degrees Celsius) because ultra-stable vitrification solutions could be used that are less prone to de-vitrification upon re-warming. This would be of particular interest for the cryopreservation of large organs or even whole organisms (with applications such as suspended animation and cryonics).

Two major reviews of cryoprotectant toxicity were published in the last 5 years; Gregory Fahy’s “Cryoprotectant Toxicity Neutralization” (Cryobiology, 2010) and Benjamin Best’s “Cryoprotective Toxicity: Facts, Issues, and Questions” (Rejuvenation Research, 2015).

Greg Fahy’s paper is a rigorous exposition of experimental results concerning the phenomenon of cryoprotectant toxicity neutralization. The paper is mostly limited to the discovery that DMSO can block the toxic effects of amides such as formamide. The combination of DMSO and formamide (or other amides such as urea and acetamide) is indeed one of the building blocks of M22 but this combination cannot be used without limit and the paper includes data that indicate the maximum molar concentrations (and ratios) that still permit full viability. In theory, if two (or more) cryoprotectants would completely neutralize each other’s toxicity they could be the sole components of a vitrification solution. But as the formulation of M22 shows, it is still necessary to add weak glass formers such as ethylene glycol, extracellular CPA’s, and “ice blockers” to supplement the toxicity neutralization obtained with formamide and DMSO. An important finding in Fahy’s paper is that n-methylation abolishes toxicity neutralization for amides and combining methylated amides also does not lead to toxicity neutralization between them. In fact, Fahy found that the presence of n-methylated compounds renders even small amounts of DMSO toxic. The remainder of the paper discusses the mechanisms of cryoprotectant toxicity and Fahy now favors protein denaturation as a plausible mechanism of (non-specific) toxicity. While other cases of toxicity neutralization have been reported in the literature, no rigorous studies have been done to produce a body of knowledge that is comparible to what we know about amide-DMSO interactions.

Benjamin Best’s paper is more general in scope but presents a lot of experimental data and also critically discusses Fahy’s work on cryoprotectant toxicity. As Ben Best points out, different (and seemingly contradictory) results do not necessarily mean that cryoprotectant toxicity is a species or cell-type dependent phenomenon. One could imagine a meta-analysis of cryobiology data in which variables such as concentration, loading- and unloading protocols, exposure temperature, exposure time, and the type of viability assay are matched to ensure methodological consistency. It is also important to compare cryoprotectants at their minimum concentration to vitrify to make meaningful toxicity comparisons. If the work at 21st Century Medicine is an indication, universal low-toxicity cryoprotective solutions should be feasible. Perhaps the most interesting part of the paper is where Best offers a critique of Grag Fahy’s “qv* hypothesis of cryoprotectant toxicity”, which aims to show that non-specfic toxicity concerns the degree to which cryoprotectants leave water available to hydrate macromolecules. This discovery allowed for the substitution of ethylene glycol for propylene glycol in Fahy’s lower toxicity vitrification solutions, despite the resulting higher CPA concentrations. Best observes, “it seems contradictory that water remains available for hydration, but not available for ice formation.” A potential rejoinder to this observation is that so called “bound water” does not participate in ice formation but can be disturbed by strong glass formers. Best also suggests a potential refinement of qv* that allows for more precise calculation of the hydrogen bonding strength of the polar groups that are used to calculate qv*. It is conceivable that such a refinement would eliminate the few remaining outliers in the data that support the qv* hypothesis. The paper also draws attention to the possibility of kosmotropic co-solvents and changes of pH and microenvironment polarity to mitigate cryoprotectant toxicity.

Neither of the papers discusses cryopreservation of the mammalian brain, but there is good reason to believe that in the case of this organ modification of low-toxicity vitrification solutions is required. Conventional cryoprotective agents such as PG, EG, and DMSO have poor blood brain barrier (BBB) penetration and the brain may not tolerate the CPA exposure times that other organs do. For example, while M22 can be used for cryopreservation of the brain, many of its component have poor BBB penetration and PVP and the ice blockers (X-1000 and Z-1000) are assumed not to cross the (non-ischemic) BBB at all. One potential solution is to (reversibly) open the BBB with so- called BBB modifying agents like detergents or perhaps to search for cryoprotective agents that can cross the BBB.

The most fundamental question in the design of vitrification solutions remains whether it is possible at all to introduce high concentrations of cryoprotectants without creating any kind of irreversible molecular and ultrastructural adverse effects. Understanding what specific and non-specific cryoprotectant toxicity exactly is should enable us to answer this question.

Originally published as a column (Quod incepimus conficiemus) in Cryonics magazine, September-October, 2016

09. February 2016 · Comments Off on Groundbreaking Scientific Results Prove that the Proposition of Human Medical Biostasis has Potential and Needs to be Brought into Mainstream Scientific and Medical Focus · Categories: Cryonics, News

Breaking News [Media Press Package with additional detail]

A team from 21st Century Medicine has developed a technology that has been independently verified to enable near-perfect, long-term structural preservation of a whole intact mammalian brain.

This new breakthrough just won the Brain Preservation Prize – five years after it was launched by the Brain Preservation Foundation (BPF).

“One of the, if not THE, most important scientific results in the history of medical biostasis and cryonics has been accomplished” Aschwin de Wolf, President of The Institute for Evidence-Based Cryonics

According to the BPF, 21st Century Medicine narrowly beat a team led by Dr. Shawn Mikula at the Max Planck Institute of Neurobiology (published last year in Nature Methods).

In addition to proof of this accomplishment and the full 21st Century Medicine “Aldehyde-Stabilized Cryopreservation” protocol recently being published in the journal Cryobiology, it was also independently verified by the BPF through extensive electron microscopic examination.

 

 

 

 

 

The prize was independently judged by neuroscientists Dr. Sebastian Seung, Professor at Princeton University and Dr. Kenneth Hayworth, President of the BPF.

“Imagine being able save, and at low temperatures, indefinitely preserve people who can no longer be sustained by contemporary medicine so that future medicine can both revive them and restore their health – these results provide strong support of that being possible”

Dr. JP de Magalhães, Chair of the UK Cryonics and Cryopreservation Research Network

This follows recent scientific evidence that long-term memory is not modified by the process of whole organism cryopreservation and revival in simple animal models.

As the two leading think-tanks/scientific networks in cryonics we share here a brief with both more color and our perspectives on what this important breakthrough means and – does not mean – for cryonics. 

In the words of Dr. Ken Hayworth, President of the Brain Preservation Foundation, and one of the prize judges:

“Every neuron and synapse looks beautifully preserved across the entire brain. Simply amazing given that I held in my hand this very same brain when it was a vitrified glassy solid… This is not your father’s cryonics”

09. February 2016 · Comments Off on Recent developments relevant to cryonics · Categories: Cryonics, Neuroscience

A lot of interesting pieces related to cryonics have appeared over the last few months that I thought I would share:

Four professors conclude in MIT Technology Review that there is significant and growing body of evidence in support of human cryopreservation: “The Science Surrounding Cryonics” 

New York Times Cover story by Pulitzer Prize winning journalist on “A Dying 23 Year Young Woman’s Hope in Cryonics and a Future”

Skeptic Michael Sherman writes a piece in Scientific American called  “Can Our Minds Live Forever?”

Here are three recent important peer reviewed papers:

Dr. Greg Fahy and Robert McIntyre of 21st Century Medicine describe here a new cryobiological and neurobiological technique, aldehyde-stabilized cryopreservation (ASC), which demonstrates the relevance and utility of advanced cryopreservation science for the neurobiological research community. The ASC technology is now also competing against Dr Mikula at Max Planck in he brain preservation prize.

The Grand Challenges of Organ Banking and It’s Potential is described by large group of the worlds leading cryobiology scientists:  The first Organ Banking Summit was convened from Feb. 27 – March 1, 2015 in Palo Alto, CA, with events at Stanford University, NASA Research Park, and Lawrence Berkeley National Labs. Experts at the summit outlined the potential public health impact of organ banking, discussed the major remaining scientific challenges that need to be overcome in order to bank organs, and identified key opportunities to accelerate progress toward this goal. Many areas of public health could be revolutionized by the banking of organs and other complex tissues, including transplantation, oncofertility, tissue engineering, trauma medicine and emergency preparedness, basic biomedical research and drug discovery – and even space travel.

Persistence of Long-Term Memory in Vitrified and Revived Caenorhabditis elegans. Two scientists ask the question:  “Can memory be retained after cryopreservation?” and then demonstrate that a form of long-term memory in C. elegans is not been modified by the process of vitrification or slow freezing.

06. January 2016 · Comments Off on Who speaks for the dead? · Categories: Cryonics, Society

Do the dead have rights, in the proper sense of the word? That is to say, when someone is obligated to do something with a dead person, like bury them, for whose benefit are they doing it? For the dead? Or for the living?

You might well ask, is this really important? In short, yes. The person to whom the obligation is owed is the person who may sue for enforcement of that right, and their identity may also determine the remedies which are available to them (be it money, compulsory performance of or abstinence from a particular act). So, the question of whose rights are engaged in dealing with the dead is fundamentally important from the cryonics patient advocate’s perspective.

An illustration: If you make a contract with someone, both of you intending that a substantial portion of what you have promised to do will only be done after (and in fact as a result of) your legal death, and vice versa that a substantial portion of what they have promised to do will likewise only be done after your legal death: who has promised what to whom?

While you remain alive, the answer seems quite obvious. But once you are dead, you are no longer a person. You, sadly, are not an entity recognized by law. You are your estate. Your estate has legal personality of a kind, but it is probably better to think of your estate as a medium. And, as such, it really isn’t about you anymore — it’s about your stuff, and who gets it. Yes, you can (and should, and hopefully do) have a will that references your cryonics arrangements, but practically speaking, the interest that your estate has in that contract you made for things to be done for you after you died, is the fact that something about that contract could result in more stuff for the estate’s beneficiaries. That’s really all the estate can care about, because the real, live person who was capable of having immaterial (or better still, “non-pecuniary”) interests in the contract is now gone.

But wait? How can the cryopreservation agreement (cat’s out of the bag — that contract was about cryonics after all) result in more stuff for the estate? Your cryonics service provider (CSP) didn’t promise to give anything, or pay anything. You, the patient promised to give something, and in fact cleverly entered into other contracts with other people to automatically transfer money to your CSP upon your legal death. So how could the cryopreservation agreement possibly represent a source of “stuff ” for the estate? Well, that’s because there were really two layers of promises — two sets of obligations in every contract. The top layer, or primary obligations, are what you actually bargained for. The secondary obligations are what the other party must do (or rather, pay) if they do not perform their primary obligations. These secondary obligations are the damages, and they are a part of the contract from the very beginning without anything being written about them.

So, the potential pecuniary ($) interest your estate has in the cryopreservation agreement, since your estate is just a medium that can only really have an interest in things and stuff, is in the failure of your CSP to do what it promised to do for you. And unfortunately for you, in cryonics there are no do-overs.

Hence why it is important to know who speaks for you when you are dead. The beneficiaries of your will, however friendly to your arrangements and well-intentioned they are, have no vested, personal, legal interest in the CSP’s performance of its primary obligations to you under the cryopreservation agreement. The executor of your will, on the other hand, has certain obligations to carry out promises made by you when you were alive, and (sometimes) to ensure that your body is dealt with as you directed by will or other instrument. The executor may even have an obligation to ensure that you remain interred as directed. But how long must they keep vigil? When they, too, are dead, does their executor now watch over the both of you? At a certain point (if not right away) this clearly becomes impossibly impractical. Alternately, if your CSP’s custody of your body was effected by a consent to body donation for research (which is the more robustly enforceable method, generally), even your executor has essentially no standing with respect to your body. And this is good, because above all else we trust that our CSPs want the same thing we want — and I have no reason to believe that is anything but true. But what if, someday down the road when your executor and next-of-kin are now in the dewar next to you, your CSP’s performance dips demonstrably below the threshold of “good faith best efforts”? Is there anyone who can claim authority to move you or to enforce performance of your CSP’s primary obligations under the cryopreservation agreement?

The above is not an exhaustive analysis by any measure. I write it hoping only that it will illustrate how peculiarly vulnerable cryonics patients are under the laws currently applying to them. What I plan to do with this column is explore intersections of law and cryonics & life extension (and there are many), and one theme I expect to visit frequently is cryonics patient advocacy. This is the issue of “who speaks for the dead” adverted to above, though in truth it starts long before legal death, and is more about how the dead or incapacitated can speak for themselves through legally recognized documentary evidence of their intentions: wills, trusts, powers of attorney (financial and health care), advance directives, consents to body donation, etc. However, all of these need agents to carry them out, and others still may seek to tear them down, so the more complex questions deal with how to build checks and balances into your supplementary cryonics documents and otherwise incentivize compliance of possible threats.

One specific topic I plan to look at soon: Just how uniform is the Uniform Anatomical Gift Act in its implementation by the various States? Are body donation consent forms executed under the authority of the UAGA enforceable outside America?

Another, somewhat related question: If a cryonicist executes a valid will in Oregon, moves to California, and dies there without executing a new will, but the original will does not comply with the formalities of execution applying in California, is the will valid — and if so, is it valid for all purposes, or only some? This is the domain of private international law, aka “conflict of laws,” which refers to how one legal jurisdiction deals with foreign legal elements: foreign parties, parties asking for application of foreign law, or foreign judgments. This is a particularly complicated area, but one which cannot be ignored, since so many cryonicists do not live in the same legal jurisdiction as their cryonics organization.

Another theme I will be exploring in this column is access to cryonics and other forms of life extension. In the case of cryonics, impediments to access can take the very blatant form of a law directly prohibiting it, or essential procedures thereof, or else operate indirectly, like mandatory autopsy provisions. Access to cryonics is also context-specific — taking on a very different meaning for someone diagnosed with a brain-threatening disorder, for instance. As such, the availability of legal assistance in dying is a topic which might be dealt with under this heading, and whether the practical benefits accruing to those patients outweighs the risks, both individually and to cryonics generally. How the law defines death, and public policy debates over whether to move to new definitions for reasons quite separate from cryonics, also fall neatly here.

Access to life extension, more generally, is also interesting to examine from a legal perspective. Are the current models of regulation applying to drug development sufficiently flexible to accommodate the advent of SENS-type rejuvenation therapies? One could say that cryonics aspires to being ordinary health care someday, at which time we can expect that it will be subject to some form of regulation. What should it look like? And how can cryonics organizations today best self-monitor and self-regulate to ease that eventual transition?

Finally, constitutional rights instruments have immense potential as tools for securing meaningful access to cryonics and other forms of life extension. However, the content and implementation of these fundamental rights documents vary throughout the world. Cryonics has fairly deep roots in America, but are we certain there is no better soil on Earth in which it might flourish?

All of the above areas of law overlap and interact, and there are other relevant ones that I have not mentioned (insurance law, notably), and no doubt a few I am not yet even aware of. I also plan to report on live cases of interest, as they arise.

One last, but significant point: due to variations between the laws of different jurisdictions (even within a single nation) you cannot simply assume that paperwork designed to work in one jurisdiction will work as intended in yours. You need to find a cryonics-friendly advisor where you live and have them review your cryonics arrangements, and revise them if necessary to work in your home jurisdiction. You are fighting for your life — you cannot afford to wear ill-fitting armor.

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

06. May 2015 · Comments Off on Cryonics as a measure of rationality? · Categories: Cryonics, Society

Most cryonics advocates are often frustrated by the amount irrationality, ignorance, and hostility when other people encounter the idea of human cryopreservation. It should not be surprising then that some of us have simply concluded that most people “just don’t get it.” Which raises an important question. Is making cryonics arrangements a strong measure of rationality? After all, a close examination of Alcor members indicates that most of them are highly educated, a disproportionate number of them have PhDs, and their backgrounds are often in fields where strong analytic skills are required; computer science, neuroscience, biochemistry, etc. Another indicator is that cryonics is relatively popular in communities with a high proportion of “nerds.” In fact, a number of “leaders” in the “rationality” community (Robin Hanson, Eliezer Yudkowsky) have cryonics arrangements and have made public arguments in favor of cryonics. In short, someone who has made cryonics arrangements is not prone to short term gratification and minimizes cognitive biases, one could argue.

The problem with this characterization of cryonics as a measure of rationality is that it does not explain why the overwhelming number of people who can be considered highly analytical or rational have not made cryonics arrangements. Many cryonicists are smart but most smart people are not cryonicists. To explain this we will have to look elsewhere.

The 18th century skeptic and analytical philosopher David Hume once wrote that “reason is a slave to the passions.” In the case of cryonics, no matter how smart a person is, if the person does not have a passion for life (and an aversion to death and aging) that person will not be primed for an enthusiastic personal endorsement of cryonics. Closely related to having a desire to live and to pursue life extension is a an optimistic temperament. A cryonicist is not necessarily “wildly” optimistic, but (s)he should at least think that life is worth living and not be prone to thinking about the future in dystopian terms. I am also inclined to think that such a person is prone to think “like an economist” (to use Bryan Caplan’s phrase). With this I mean that a person can think in a probabilistic manner, does not see the world as a “zero-sum game,” and sees developments like automation, computerisation and biotechnologies in a positive light.

Do these combined traits produce a favorable attitude towards cryonics? This still cannot be the complete story because the traits discussed so far are shared by many millions of people in the world and support for cryonics is extremely small. I want to single out two additional traits that are usually required to prime someone for cryonics. The person also needs to be a non-conformist of some kind. When cryonics is as small as it is, strongly endorsing cryonics makes someone stand out (to put it mildly). And this “standing out” is not comparable to just having a bizarre hobby or a strange sense of style. It can sometimes produce confusion or hostility in other people, which can turn even our most life-affirming friends and family into apologetic pro-mortalists.

The most important trait, in my opinion, and the one that really distinguishes the cryonicist from the non-cryonicist, is the ability to deal with vulnerability, uncertainty and the unknown — in some cases, to even welcome it. People who have been around in cryonics for awhile know that ultimately (that is, when you dig a little deeper) skeptics are really afraid to be resuscitated in a distant and unknown future. This should not be easily dismissed. Personal identity is not identical to the brain or the body (as a simplistic version of cryonics would have it) but extends to all the things and people that have become part of a person’s life. To many people, the cryonics proposal means  survival at the cost of losing everything that gives meaning to their lives.

If we look at the limited acceptance of cryonics from this perspective, does this inspire optimism in persuading more people? An immediate response would be negative because fundamental character traits are hard to change. Another approach, however, is to change the conceptualization and delivery of cryonics so that these fears are not triggered. In particular, it might serve a cryonics organization well to transition from an organization that just “stores” a human body or brain without specific resuscitation and reintegration scenarios to an organization that offers more comprehensive means of identity preservation. Such an organization puts a strong emphasis on the cryopreservation of families and friends. It will offer means of asset preservation and personal belongings. It develops specific resuscitation protocols which are updated and calibrated as our knowledge and technologies improve. And it makes serious efforts to provide a reintegration program which seeks to minimize adjustment to the time in which an individual is resuscitated.

Is endorsement of cryonics a measure of rationality? Yes, but without a desire to live, a reasonably optimistic attitude, an independent mindset, and, most of all, confidence in a cryonics organization to preserve all that is important to a person, being smart by itself is not going to do it.

This is a web-exclusive edition of the Quod incepimus conficiemus column that is published in Cryonics magazine but was omitted from the April 2015 issue.

13. February 2015 · Comments Off on Though She Isn’t Really Ill, There’s a Little Yellow Pill… · Categories: Health, Neuroscience, Society

Humans have been ingesting mindand mood-altering substances for millennia, but it has only rather recently become possible to begin to elucidate drug mechanisms of action and to use this information, along with our burgeoning knowledge of neuroscience, to design drugs intended to have a specific effect. And though most people think of pharmaceuticals as “medicine,” it has become increasingly popular to discuss the possibilities for the use of drugs in enhancement, or improvement of “human form or functioning beyond what is necessary to sustain or restore good health” (E.T. Juengst; in Parens, 1998, p 29).

Some (transhumansits) believe that enhancement may not only be possible, but that it may even be a moral duty. Others (bioconservatives) fear that enhancement may cause us to lose sight of what it means to be human altogether. It is not the intention of this article to advocate enhancement or to denounce it. Instead, let’s review some of the drugs (and/or classes of drugs) that have been identified as the most promisingly cognitive- or mood-enhancing. Many of the drugs we will cover can be read about in further depth in Botox for the brain: enhancement of cognition, mood and pro-social behavior and blunting of unwanted memories (Jongh, R., et al., Neuroscience and Biobehavioral Reviews 32 (2008): 760-776).

Of most importance in considering potentially cognitive enhancer drugs is to keep in mind that, to date, no “magic bullets” appear to exist. That is, there are no drugs exhibiting such specificity as to have only the primary, desired effect. Indeed, a general principle of trade-offs (particularly in the form of side effects) appears to exist when it comes to drug administration for any purpose, whether treatment or enhancement. Such facts may constitute barriers to the practical use of pharmacological enhancers and should be taken into consideration when discussing the ethics of enhancement.

Some currently available cognitive enhancers include donepezil, modafinil, dopamine agonists, guanfacine, and methylphenidate. There are also efforts underway to develop memory-enhancing drugs, and we will discuss a few of the mechanisms by which they are proposed to act. Besides cognitive enhancement, the enhancement of mood and prosocial behavior in normal individuals are other types of enhancement that may be affected pharmacologically, most usually by antidepressants or oxytocin. Let’s briefly cover the evidence for the efficacy of each of these in enhancing cognition and/or mood before embarking on a more general discussion of the general principles of enhancement and ethical concerns.

One of the most widely cited cognitive enhancement drugs is donepezil (Aricept®), an acetylcholinesterase inhibitor. In 2002, Yesavage et al. reported the improved retention of training in healthy pilots tested in a flight simulator. In this study, after training in a flight simulator, half of the 18 subjects took 5 mg of donepezil for 30 days and the other half were given a placebo. The subjects returned to the lab to perform two test flights on day 30. The donepezil group was found to perform similarly to the initial test flight, while placebo group performance declined. These results were interpreted as an improvement in the ability to retain a practiced skill. Instead it seems possible that the better performance of the donepezil group could have been due to improved attention or working memory during the test flights on day 30.

Another experiment by Gron et al. (2005) looked at the effects of donepezil (5 mg/day for 30 days) on performance of healthy male subjects on a variety of neuropsychological tests probing attention, executive function, visual and verbal short-term and working memory, semantic memory, and verbal and visual episodic memory. They reported a selective enhancement of episodic memory performance, and suggested that the improved performance in Yesavage et al.’s study is not due to enhanced visual attention, but to increased episodic memory performance.

Ultimately, there is scarce evidence that donepezil improves retention of training. Better designed experiments need to be conducted before we can come to any firm conclusions regarding its efficacy as a cognitive-enhancing.

The wake-promoting agent modafinil (Provigil®) is another currently available drug that is purported to have cognitive enhancing effects. Provigil® is indicated for the treatment of excessive daytime sleepiness and is often prescribed to those with narcolepsy, obstructive sleep apnea, and shift work sleep disorder. Its mechanisms of action are unclear, but it is supposed that modafinil increases hypothalamic histamine release, thereby promoting wakefulness by indirect activation of the histaminergic system. However, some suggest that modafinil works by inhibiting GABA release in the cerebral cortex.

In normal, healthy subjects, modafinil (100-200 mg) appears to be an effective countermeasure for sleep loss. In several studies, it sustained alertness and performance of sleep-deprived subjects(up to 54.5 hours) and has also been found to improve subjective attention and alertness, spatial planning, stop signal reaction time, digit-span and visual pattern recognition memory. However, at least one study (Randall et al., 2003) reported “increased psychological anxiety and aggressive mood” and failed to find an effect on more complex forms of memory, suggesting that modafinil enhances performance only in very specific, simple tasks.

The dopamine agonists d-amphetamine, bromocriptine, and pergolide have all been shown to improve cognition in healthy volunteers, specifically working memory and executive function. Historically, amphetamines have been used by the military during World War II and the Korean War, and more recently as a treatment for ADHD (Adderall®). But usage statistics suggest that it is commonly used for enhancement by normal, healthy people—particularly college students.

Interestingly, the effect of dopaminergic augmentation appears to have an inverted U-relationship between endogenous dopamine levels and working memory performance. Several studies have provided evidence for this by demonstrating that individuals with a low workingmemory capacity benefit from greater improvements after taking a dopamine receptor agonist, while high-span subjects either do not benefit at all or show a decline in performance.

Guanfacine (Intuniv®) is an α2 adrenoceptor agonist, also indicated for treatment of ADHD symptoms in children, but by increasing norepinephrine levels in the brain. In healthy subjects, guanfacine has been shown to improve visuospatial memory (Jakala et al., 1999a, Jakala et al., 1999b), but the beneficial effects were accompanied by sedative and hypotensive effects (i.e., side effects). Other studies have failed to replicate these cognitive enhancing effects, perhaps due to differences in dosages and/or subject selection.

Methylphenidate (Ritalin®) is a well-known stimulant that works by blocking the reuptake of dopamine and norepinephrine. In healthy subjects, it has been found to enhance spatial workingmemory performance. Interestingly, as with dopamine agonists, an inverted U-relationship was seen, with subjects with lower baseline working memory capacity showing the greatest improvement after methylphenidate administration.

Future targets for enhancing cognition are generally focused on enhancing plasticity by targeting glutamate receptors (responsible for the induction of long-term potentiation) or by increasing CREB (known to strengthen synapses). Drugs targeting AMPA receptors, NMDA receptors, or the expression of CREB have all shown some promise in cognitive enhancement in animal studies, but little to no experiments have been carried out to determine effectiveness in normal, healthy humans.

Beyond cognitive enhancement, there is also the potentialfor enhancement of mood and pro-social behavior. Antidepressants are the first drugs that come to mind when discussing the pharmacological manipulation of mood, including selective serotonin reuptake inhibitors (SSRIs). Used for the treatment of mood disorders such as depression, SSRIs are not indicated for normal people of stable mood. However, some studies have shown that administration of SSRIs to healthy volunteers resulted in a general decrease of negative affect (such as sadness and anxiety) and an increase in social affiliation in a cooperative task. Such decreases in negative affect also appeared to induce a positive bias in information processing, resulting in decreased perception of fear and anger from facial expression cues.

Another potential use for pharmacological agents in otherwise healthy humans would be to blunt unwanted memories by preventing their consolidation.Thismay be accomplished by post-training disruption of noradrenergic transmission (as with β-adrenergic receptor antagonist propranolol). Propranolol has been shown to impair the long-term memory of emotionally arousing stories (but not emotionally neutral stories) by blocking the enhancing effect of arousal on memory (Cahill et al., 1994). In a particularly interesting study making use of patients admitted to the emergency department, post-trauma administration of propranolol reduced physiologic responses during mental imagery of the event 3 months later (Pitman et al., 2002). Further investigations have supported the memory blunting effects of propranolol, possibly by blocking the reconsolidation of traumatic memories.

GENERAL PRINCIPLES

Reviewing these drugs and their effects leads us to some general principles of cognitive and mood enhancement. The first is that many drugs have an inverted U-shaped dose-response curve, where low doses improve and high doses impair performance.This is potentially problematic for the practical use of cognition enhancers in healthy individuals, especially when doses that are most effective in facilitating one behavior simultaneously exert null or detrimental effects on other behaviors.

Second, a drug’s effect can be “baseline dependent,” where low-performing individuals experience greater benefit from the drug while higher-performing individuals do not see such benefits (which might simply reflect a ceiling effect), or may, in fact, see a deterioration in performance (which points to an inverted U-model). In the case of an inverted U-model, low performing individuals are found on the up slope of the inverted U and thus benefit from the drug, while high-performing individuals are located near the peak of the inverted U already and, in effect, experience an “overdose” of neurotransmitter that leads to a decline in performance.

Trade-offs exist in the realm of cognitive enhancing drugs as well. As mentioned, unwanted “side effects” are often experienced with drug administration, ranging from mild physiological symptoms such as sweating to more concerning issues like increased agitation, anxiety, and/or depression.

More specific trade-offs may come in the form of impairment of one cognitive ability at the expense of improving another. Some examples of this include the enhancement of long-term memory but deterioration of working memory with the use of drugs that activate the cAMP/protein kinase A (PKA) signaling pathway. Another tradeoff could occur between the stability versus the flexibility of long-term memory, as in the case of certain cannabinoid receptor antagonists which appear to lead to more robust long-term memories, but which also disrupt the ability of new information to modify those memories. Similarly, a trade-off may exist between stability and flexibility of working memory. Obviously, pharmacological manipulations that increase cognitive stability at the cost of a decreased capacity to flexibly alter behavior are potentially problematic in that one generally does not wish to have difficulty in responding appropriately to change.

Lastly, there is a trade-off involving the relationship between cognition and mood. Many mood-enhancing drugs, such as alcohol and even antidepressants, impair cognitive functioning to varying degrees. Cognition-enhancing drugs may also impair emotional functions. Because cognition and emotion are intricately regulated through interconnected brain pathways, inducing change in one area may have effects in the other. Much more research remains to be performed to elucidate these interactions before we can come to any firm conclusions.

ETHICAL CONCERNS

Again, though it is not the place of this article to advocate or denounce the use of drugs for human enhancement, obviously there are considerable ethical concerns when discussing the administration of drugs to otherwise healthy human beings. First and foremost, safety is of paramount importance. The risks and side-effects, including physical and psychological dependence, as well as long-term effects of drug use should be considered and weighed heavily against any potential benefits.

Societal pressure to take cognitive enhancing drugs is another ethical concern, especially in light of the fact that many may not actually produce benefits to the degree desired or expected. In the same vein, the use of enhancers may give some a competitive advantage, thus leading to concerns regarding fairness and equality (as we already see in the case of physical performance-enhancing drugs such as steroids). Additionally, it may be necessary, but very difficult, to make a distinction between enhancement and therapy in order to define the proper goals of medicine, to determine health-care cost reimbursement, and to “discriminate between morally right and morally problematic or suspicious interventions” (Parens, 1998). Of particular importance will be determining how to deal with drugs that are already used off-label for enhancement. Should they be provided by physicians under certain conditions? Or should they be regulated in the private commercial domain?

There is an interesting argument that using enhancers might change one’s authentic identity—that enhancing mood or behavior will lead to a personality that is not really one’s own (i.e., inauthenticity), or even dehumanization—while others argue that such drugs can help users to “become who the really are,” thereby strengthening their identity and authenticity. Lastly, according to the President’s Council on Bioethics, enhancement may “threaten our sense of human dignity and what is naturally human” (The President’s Council, 2003). According to the Council, “the use of memory blunters is morally problematic because it might cause a loss of empathy if we would habitually ‘erase’ our negative experiences, and because it would violate a duty to remember and to bear witness of crimes and atrocities.” On the other hand, many people believe that we are morally bound to transcend humans’ basic biological limits and to control the human condition. But even they must ask: what is the meaning of trust and relationships if we are able to manipulate them?

These are all questions without easy answers. It may be some time yet before the ethical considerations of human cognitive and mood enhancement really come to a head, given the apparently limited benefits of currently available drugs. But we should not avoid dealing with these issues in the meantime; for there will come a day when significant enhancement, whether via drugs or technological means, will be possible and available. And though various factions may disagree about the morality of enhancement, one thing is for sure: we have a moral obligation to be prepared to handle the consequences of enhancement, both positive and negative.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, December, 2013

05. February 2015 · Comments Off on An End to the Virus · Categories: Health, Science

Breakthroughs in medicine have increased substantially over the last hundred years, and most would agree that the introduction of antibiotics in 1942 has been one of the largest milestones in the history of medicine thus far. The success in treating bacterial infection has only accentuated the glaring lack of progress in developing effective therapeutics for those other enemies of the immune system, viruses. But Dr. Todd Rider and his team at MIT have dropped a bombshell with their announcement of a new broad spectrum antiviral therapeutic, DRACO, which appears not only to cure the common cold, but to halt or prevent infections by all known viruses.

Before talking specifically about this exciting news, let us first review viral biology and why viral infections have been so difficult to treat.

As you may recall from your early education, a virus particle, or virion, consists of DNA or RNA surrounded only by a protein coat (i.e., naked virus) or, occasionally, a protein coat and a lipid membrane (i.e., enveloped virus). Viruses have no organelles or metabolism and do not reproduce on their own, so they cannot function without using the cellular machinery of a host (bacteria, plant, or animal).

Viruses can be found all throughout our environment and are easily picked up and transferred to areas where they may enter our bodies, usually through the nose, mouth, or breaks in the skin. Once inside the host, the virus particle finds a host cell to infect so it can reproduce.

There are two ways that viruses reproduce. The first way is by attaching to the host cell and entering it or injecting viral DNA/RNA into the cell. This causes the host cell to make copies of the viral DNA and translate that DNA to make viral proteins. The host cell assembles new viruses and releases them when the cells break apart and die, or it buds the new viruses off, which preserves the host cell. This approach is called the lytic cycle.

The second way that viruses reproduce is to use the host cell’s own materials. A viral enzyme called reverse transcriptase makes a segment of DNA from its RNA using host materials. The DNA segment gets incorporated into the host cell’s DNA. There, the viral DNA lies dormant and gets reproduced with the host cell. When some environmental cue happens, the viral DNA takes over, makes viral RNA and proteins, and uses the host cell machinery to assemble new viruses. The new viruses bud off. This approach is called the lysogenic cycle; these viruses are called retroviruses and include herpes viruses and HIV.

Once free from the host cell the new viruses can attack other cells and produce thousands more virus particles, spreading quickly throughout the body. The immune system responds quickly by producing proteins to interfere with viral replication, pyrogenic chemicals to raise body temperature, and the induction of cell death (apoptosis). In some cases simply continuing the natural immune response is enough to eventually halt viral infection. But the virus kills many host cells in the meantime, leading to symptoms ranging from the characteristic runny nose and sore throat of a cold (rhinovirus) to the muscle aches and coughing associated with the flu (influenza virus).

Any virus can be deadly, especially to hosts with a weakened immune system, such as the elderly, small children, and persons with AIDS (though death is actually often due to a secondary bacterial infection). And any viral infection will cause pain and suffering, making treatment a very worthwhile goal. So far, the most successful approach to stopping viral infections has been prevention through the ubiquitous use of vaccines. The vaccine— either a weakened form of a particular virus or a mimic of one—stimulates the immune system to produce antibodies specific to that virus, thereby preventing infection when the virus is encountered in the environment. In another approach, antiviral medications are administered post-infection and work by targeting some of the specific ways that viruses reproduce.

However, viruses are very difficult to defeat. They vary enormously in genetic composition and physical conformation, making it difficult to develop a treatment that works for more than one specific virus. The immense number of viral types in nature makes even their classification a monumental job as there is more enormous structural diversity among viruses. Viruses have been evolving much longer than any cells have even existed and they have evolved methods to avoid detection and to overcome attempts to block replication. So, while we have made some progress in individual battles, those pesky viruses have definitely been winning the war.

Which is why the announcement of a broad spectrum antiviral therapeutic agent is such huge news. In their paper, Rider et al. describe a drug that is able to identify cells infected by any type of virus and which is then able to specifically kill only the infected cells to terminate the infection. The drug, named DRACO (which stands for Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer), was tested against 15 viruses including rhinoviruses, H1N1 influenza, polio virus, and several types of hemorrhagic fever. And it was effective against every virus it was pitted against.

Dr. Rider looked closely at living cells’ own defense mechanisms in order to design DRACO. First, he observed that all known viruses make long strings of doublestranded RNA (dsRNA) during replication inside of a host cell, and that dsRNA is not found in human or other cells. As part of the natural immune response, human cells have proteins that latch onto dsRNA and start a biochemical cascade that prevents viral replication. But many viruses have evolved to overcome this response quite easily. So Rider combined dsRNA detection with a more potent weapon: apoptosis, or cell suicide.

Basically, the DRACO consists of two ends. One end identifies dsRNA and the other end induces cells to undergo apoptosis. When the DRACO binds to dsRNA it signals the other end of the DRACO to initiate cell suicide, thus killing the infected cell and terminating the infection. Beautifully, the DRACO also carries a protein that allows it to cross cell membranes and enter any human or animal cell. But if no dsRNA is present, it simply does nothing, leaving the cell unharmed.

An interesting question is whether any viruses are actually beneficial and whether wiping all viruses out of an organismal system may have negative consequences (as happens when antibiotic treatment eradicates both invading pathogenic bacteria and non-pathogenic flora, often leading to symptoms such as digestive upset). After his recent presentation at the 6th Strategies for Engineered Negligible Senescence (SENS) conference in September 2013, Dr. Rider fielded this question and stated quite adamantly that there are no known beneficial, symbiotic, or non-harmful viruses. This point is further emphasized in a recently published interview in which he is asked whether DRACO-triggered cell death could lead to a lesion in a tissue or organ. Rider responds that “Virtually all viruses will kill the host cell on the way out. Of the hand-full that don’t, your own immune system will try to kill those infected cells. So we’re not really killing any more cells with our approach than we already have been. It’s just that we’re killing them at an early enough stage before they infect and ultimately kill more cells. So, if anything, this limits the amount of cell death.”

So far, DRACO has been tested in cellular culture and in mouse models against a variety of very different virus types. Rider hopes to license DRACO to a pharmaceutical company so that it can be assessed in larger animal trials and, ultimately, human trials. Unfortunately, it may take a decade or more to complete this process and make the drug available for human therapeutic purposes, and that’s only if there is enough interest to do so. Amazingly, the DRACO project was started over 11 years ago and has barely survived during that period due to lack of interest and funding. Even now, after the DRACOs have been successfully engineered, produced, and tested, no one has yet reached out to Rider about taking them beyond the basic research stage. Let us hope that those of us who do find this work unbelievably exciting can make enough noise that Rider’s work continues to the benefit of all mankind.

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, November, 2013

03. February 2015 · Comments Off on No More Couch Potato · Categories: Health

In my review of The SharpBrains Guide to Brain Fitness a couple of months ago, the importance of certain lifestyle choices—particularly physical exercise— to maintain and enhance brain health was emphasized at length. Intuitively, we all know that physical activity is good for us. The metaphorical “couch potato” is assumed to be a person in poor health, precisely because of his or her lack of movement (and, of course, lazily consumed snacks and mind-numbing television). But even those of us who admonish the couch potato are moving our bodies a lot less these days due to an increase in the number of jobs requiring long periods of sitting. And current research is clear: all that sitting is taking a toll on our health.

So we know we need to get up and get moving. But what kind of exercise is best? So far, cardiovascular, or aerobic, exercise has received most of the attention in the literature. Because it is light-to-moderate in intensity and long in duration, aerobic exercise increases heart rate and circulation for extended periods, which is presumed to trigger biochemical changes in the brain that spur neuroplasticity—the production of new connections between neurons and even of new neurons themselves. It appears that the best regimen of aerobic exercise incorporates, at a minimum, three 30 to 60 minute sessions per week. In short, plenty of research has found that myriad positive physical and cognitive health benefits are correlated with aerobic exercise.

But what about non-aerobic exercise, such as strength training? The truth is that very little is known about the effects of non-aerobic exercise on cognitive health. What few studies exist show a positive effect of strength training on cognitive health, but the findings are definitely less conclusive than the plethora of evidence supporting aerobic exercise.

However, a lack of research should not be interpreted as negative results. I think non-aerobic exercise has received less research attention because, well, it is harder and appears less accessible than aerobic exercise. It is probably easier to get research participants to commit to a straightforward exercise regimen that doesn’t involve a lot of explanation or study to figure out. Let’s face it: pushing pedals on a stationary bike requires less mental effort than figuring out how to perform weight-bearing exercises with good form.

At worst, we may ultimately discover that non-aerobic exercise has no cognitive benefits. But let’s not throw the baby out with the bathwater. Because strength training does, in fact, promote a number of physical effects that are of great overall benefit to health, especially to the aging individual. Indeed, one would be remiss to omit strength training from any exercise regimen designed to promote healthy aging and a long, physically fit life.

The primary, and most obvious, effect of strength training is that of muscle development, or hypertrophy. Muscles function to produce force and motion and skeletal muscles are responsible for maintaining and changing posture, locomotion, and balance. Anyone who wishes to look and feel strong, physically capable, and well-balanced would do well to develop the appropriate muscles to reach these goals. Muscle mass declines with age, so it is smart to build a reserve of muscle in a relatively youthful state and to maintain it with regular workouts for as long as possible. Doing so will stave off the functional decline known as frailty, a recognized geriatric syndrome associated with weakness, slowing, decreased energy, lower activity, and unintended weight loss.

Those who know me know that I am very, very thin. At 5 foot 9 inches, it has always been a struggle to maintain my weight above 90 lbs.—a full 40 lbs. underweight for a woman of my height. This is almost certainly due, in large part, to genetics (my parents are both rail-thin), and no amount of eating has ever worked to put on additional pounds. Over the years, I grew more concerned about what my underweight meant in terms of disease risks as I age. In particular, dual energy x-ray absorbiometry (DEXA) scans for bone mineral density at age 27 and 33 showed accelerated bone loss beyond what is normal for my age. I was on a trajectory for a diagnosis of osteoporosis by my mid-40s.

Besides ensuring adequate calcium intake, I knew that the best prescription for slowing down bone loss is to perform weight-bearing exercises. Strength training causes the muscles to pull on the bone, resulting in increased bone strength. Strength training also increases muscle strength and flexibility, which reduces the likelihood of falling—the number-one risk factor for hip fracture.

So I dusted off my long-unused gym pass and started strength training 3 to 4 times a week. I was too weak to even lift weights in the beginning, so I started with body weight exercises and gradually progressed to weight machines. Weight machines allow you to build strength and to gain an understanding of how an exercise works a particular muscle or group of muscles. Many machines also have a limited range of motion within which to perform the exercise, providing some guidance on how to perform the movement. As I made improvements in strength, I began reading about strength training exercises online and downloaded some apps to help me in the gym.

For a basic “how-to,” nothing beats a video. There are plenty of exercise demonstration videos on YouTube.com and several other sites, but I prefer the definitive (and straight-to-the-point) visual aids provided by Bodybuilding.com. They offer short instructional videos for just about every strength training exercise in existence. The videos also download quickly and play easily on a mobile device, in case you need a refresher in the gym.

There are a lot of great apps out there, too. My favorites so far include PerfectBody (and associated apps by the same developer), GymPact, and Fitocracy. PerfectBody provides weekly workout routines, complete with illustrated descriptions of exercises and the ability to track your progress by documenting weight lifted and number of repetitions (reps) for each exercise. It is an all-in-one fitness program for learning foundational exercises and building strength and confidence in the gym.

If you have a hard time committing to a workout schedule, Gympact may help. One of the latest in a series of apps that make you put your money where your mouth is, you make a Gympact agreement to go to the gym a minimum number of times per week in order to earn monetary rewards for doing so. The catch is that you are charged money if you fail to meet your pact (which helps to pay all those committed gym-goers who didn’t renege on their promises). For many, the thought of losing money can provide quite the incentive to get your tail to the gym.

Now that you’ve got exercise examples, progress tracking, and motivation to actually get to the gym, how about some fun? Fitocracy is an app that turns exercise into a game, letting you track your exercise in return for points and “level ups” like a video game. There are challenges to meet and quests to conquer, adding to the competitive game-play element. But there’s also a nice social aspect, with friends and groups enabling people to “prop” one another and to provide support and advice.

Once you start pumping iron, you may quickly realize a need for nutrition adequate to meet your new muscle-building goals. As we all know, protein is the most important nutrient for building muscle. And while I will not attempt to provide advice regarding the appropriate nutrient ratio for the calories you consume each day, I can tell you that it is generally recommended to get at least 1 gram of protein per pound of body weight per day if you want to support muscle growth.

Adequate protein consumption is necessary even if you are not strength training and becomes even more important as you age. Reduced appetite and food intake, impaired nutrient absorption, and age-related medical and social changes often result in malnourishment. An insufficient intake of protein, in particular, can lead to loss of muscle mass, reduced strength, and many other negative factors leading to frailty.

It seems that whey protein provides the ultimate benefits in this arena. Whey, which is derived from milk, is a high-quality protein supplement with a rich source of branched-chain amino acids (BCAAs) to stimulate protein synthesis and inhibit protein breakdown, helping to prevent agerelated muscle-wasting (i.e., sarcopenia). Besides muscle support, a growing number of studies indicate other positive, antiaging effects of whey such as antioxidant enhancement, anti-hypertensive effect, hypoglycemic effect, and the promotion of bone formation and suppression of bone resorption. Life Extension Foundation recently reported that these effects mimic the benefits of calorie restriction without a reduction of food intake, playing roles in hormone secretion and action, intracellular signaling, and regulation of gene transcription and translation.

There are many whey protein powder supplements on the market in a variety of formulations and flavors. Whey protein isolate is quickly absorbed and incorporated into muscles, making it a good post-workout option, whereas whey protein concentrate is absorbed and incorporated more slowly, making it ideal for consumption just before bedtime. A whey protein powder may consist of isolate only, concentrate only, or both. Choose what best meets your needs and purposes.

Flavor is an important factor to consider, as well. Most major brands offer a variety of flavors such as vanilla, chocolate, strawberry, and some exotic options. Unflavored powders are sometimes available and are a great neutral protein base for mixing into (green) smoothies or other recipes. Some whey protein powders may actually include sugars to “improve” taste, so make sure to read the ingredients. Even many zero carb powders are still quite sweet. Many brands offer sample size packets which can be very helpful in determining whether or not you like a particular flavor or overall taste prior to buying an entire container.

Lastly, consider the sources of whey protein powder ingredients carefully. Not all whey is created equal, and many commercial brands on the market derive their ingredients from dubious sources or from animals treated with hormones and living in less-than-stellar conditions. But there are many great products out there, including Life Extension’s New Zealand Whey Protein Concentrate, which is derived from grass-fed, free range cows living healthy lives in New Zealand and not treated with Growth Hormone (rBST). If you have reservations about whey protein, there are also alternative protein powders that are derived from plants or egg white.

In summary, while the jury is still out regarding the cognitive benefits of nonaerobic exercise, such exercise is still a very important part of an overall plan to support health and longevity. Adequate nutritional support in the form of whey protein supplementation is generally indicated for its many health benefits, and is absolutely integral to muscle-building efforts. At the very least, strength training should complement brain-boosting aerobic exercise and will help to stave off bone loss and frailty as you age. So erase any preconceived notions you may have had about bodybuilding and start lifting today!

Originally published as an article (in the Cooler Minds Prevail series) in Cryonics magazine, October, 2013