The biogerontologist David Sinclair and the bioethicist Leon Kass recently locked horns
in a radio debate (http://www.theconnection.org/shows/2004/01/20040106_b_main.asp) on human
life extension that was remarkable for one thing: on the key issue, Kass was right and
Sinclair wrong. Sinclair suggested, as have other experts, including his mentor Lenny
Guarente and the National Institute on Aging advisory council member Elizabeth Blackburn,
that Kass and other bioconservatives are creating a false alarm about life extension,
because only a modest (say, 30%) increase in human life span is achievable by biomedical
intervention, whereas Kass's apprehensions concern extreme or indefinite life extension.
Kass retorted that science isn't like that: modest success tends to place the bit between
our teeth and can often result in advances far exceeding our expectations.
Coping with Methuselah consists of seven essays, mostly on the economics
of life extension but also including one essay surveying the biology of aging and one on
the ethics of life extension. The economic issues addressed are wide ranging, including
detailed analysis of the balance between wealth creation by the employed and wealth
consumption in pensions and health care; most chapters focus on the United States, but the
closing chapter discusses these issues in a global context. Each essay is followed by a
short commentary by another distinguished author. Within their own scope, all of these
contributions are highly informative and rigorous. Dishearteningly, however, all echo
Sinclair's views about the limited prospects for life extension in the coming decades. In
my opinion, they make three distinct oversights.
The first concerns current science. Sinclair and several other prominent gerontologists
are presently seeking human therapies based on the long-standing observation that lifelong
restriction of caloric intake considerably extends both the healthy and total life span of
nearly all species in which it has been tried, including rodents and dogs. Drugs that
elicit the gene expression changes that result from caloric restriction might, these
workers assert, extend human life span by something approaching the same proportion as seen
in rodents—20% is often predicted—without impacting quality of life, and even when
administered starting in middle age. They assiduously stress, however, that anything beyond
this degree of life extension is inconceivable.
I agree with these predictions in two respects: that the degree of life extension
achieved by first-generation drugs of this sort may well approach the (currently unknown)
amount elicitable by caloric restriction itself in humans, and that it is unlikely to be
much exceeded by later drugs that work the same way. In two other ways, however, I claim
they are incorrect. The first error is the assumption of proportionality: I have recently
argued (de Grey 2004), from evolutionary considerations, that longer-lived species will
show a smaller maximal proportional life-span extension in response to starvation, probably
not much more than the same
absolute increase seen in shorter-lived species. The second error is the
assertion that no other type of intervention can do better. In concert with other
colleagues whose areas of expertise span the relevant fields, I have described (de Grey et
al. 2002, 2004) a strategy built around the actual
repair (not just retardation of accumulation) of age-related molecular
and cellular damage—consisting of just seven major categories of ‘rejuvenation therapy’
(Table 1)—that appears technically feasible and, by its nature, is indefinitely extensible
to greater life spans without recourse to further conceptual breakthroughs.
The second oversight made both by the contributors to
Coping with Methuselah and by other commentators is demographic. Life
expectancy is typically defined in terms of what demographers call a period survival curve,
which is a purely artificial construction derived from the proportions of those of each age
at the start of a given year who die during that year. The ‘life expectancy’ of the
‘population’ thus described is that of a hypothetical population whose members live all
their lives with the mortality risk at each age that the real people of that age
experienced in the year of interest. The remaining life expectancy of someone aged
N in that year is more than this life expectancy minus
N for two reasons: one mathematical (what one actually wants, roughly, is
the age to which the probability of survival is half that of survival to
N ) and one biomedical (mortality rates at each age, especially advanced
ages, tend to fall with time). My spirits briefly rose on reading Aaron and Harris's
explicit statement (p. 69) of the latter reason. Unfortunately, they didn't discuss what
would happen if age-specific mortality rates fell by more than 2% per year. An interesting
scenario was thus unexplored: that in which mortality rates fall so fast that people's
remaining (not merely total) life expectancy increases with time. Is this
unimaginably fast? Not at all: it is simply the ratio of the mortality rates at consecutive
ages (in the same year) in the age range where most people die, which is only about 10% per
year. I term this rate of reduction of age-specific mortality risk ‘actuarial escape
velocity’ (AEV), because an individual's remaining life expectancy is affected by aging and
by improvements in life-extending therapy in a way qualitatively very similar to how the
remaining life expectancy of someone jumping off a cliff is affected by, respectively,
gravity and upward jet propulsion (Figure 1).
The escape velocity cusp is closer than you might guess. Since we are already so long
lived, even a 30% increase in healthy life span will give the first beneficiaries of
rejuvenation therapies another 20 years—an eternity in science—to benefit from
second-generation therapies that would give another 30%, and so on ad infinitum. Thus, if
first-generation rejuvenation therapies were universally available and this progress in
developing rejuvenation therapy could be indefinitely maintained, these advances would put
us beyond AEV. Universal availability might be thought economically and sociopolitically
implausible (though that conclusion may be premature, as I will summarise below), so it's
worth considering the same question in terms of life-span
potential (the life span of the luckiest people). Figure 1 again
illustrates this: those who get first-generation therapies only just in time will in fact
be unlikely to live more than 20–30 years more than their parents, because they will spend
many frail years with a short remaining life expectancy (i.e., a high risk of imminent
death), whereas those only a little younger will never get that frail and will spend rather
few years even in biological middle age. Quantitatively, what this means is that if a 10%
per year decline of mortality rates at all ages is achieved and sustained indefinitely,
then the first 1000-year-old is probably only 5–10 years younger than the first
150-year-old.
The third oversight that I observe in contemporary commentaries on life extension, among
which
Coping with Methuselah is representative, is the most significant because
of its urgency. First-generation rejuvenation therapies, whenever they arrive, will surely
build on a string of prior laboratory achievements. Those achievements, it seems to me,
will have progressively worn down humanity's evidently desperate determination to close its
eyes to the prospect of defeating its foremost remaining scourge anytime soon. The problem
(if we can call it that) is that this wearing-down may have been completed long before the
rejuvenation therapies arrive. There will come an advance—probably a single laboratory
result—that breaks the camel's back and forces society to abandon that denial: to accept
that the risk of getting one's hopes up and seeing them dashed is now outweighed by the
risk of missing the AEV boat by inaction. What will that result be? I think a conservative
guess is a trebling of the remaining life span of mice of a long-lived strain that have
reached two-thirds of their normal life span before treatment begins. This would possess
what I claim are the key necessary features: a big life extension, in something furry and
not congenitally sick, from treatment begun in middle age.
It is the prospect of AEV, of course, that makes this juncture so pivotal. It seems
quite certain to me that the announcement of such mice will cause huge, essentially
immediate, society-wide changes in lifestyle and expenditure choices—in a word,
pandemonium—resulting from the anticipation that extreme human life extension might arrive
soon enough to benefit people already alive. We will probably not have effective
rejuvenation therapies for humans for at least 25 years, and it could certainly be 100
years. But given the present status of the therapies listed in Table 1, we have, in my
view, a high probability of reaching the mouse life extension milestone just described
(which I call ‘robust mouse rejuvenation’) within just
ten years, given adequate and focused funding (perhaps $100 million per
year). And nobody in
Coping with Methuselah said so. This timeframe could be way off, of
course, but as Wade notes (p. 57), big advances often occur much sooner than most experts
expect. Even the most obvious of these lifestyle changes—greater expenditure on traditional
medical care, avoidance of socially vital but risky professions—could severely destabilise
the global economy; those better versed in economics and sociology than I would doubtless
be even more pessimistic about our ability to negotiate this period smoothly.
Overpopulation, probably the most frequently cited drawback of curing aging, could not
result for many decades, but the same cannot be said for breadth of access irrespective of
ability to pay: in a post-9/11 world, restricted availability of rejuvenation therapies
resembling that seen today with AIDS drugs would invite violence on a scale that, shall we
say, might be worth trying to avoid.
Am I, then, resigned to a future in which countless millions are denied many decades of
life by our studied reluctance to plan ahead today? Not quite. The way out is pointed to in
Lee and Tuljapurkar's (1997) graph of the average wealth consumed and generated by an
individual as a function of age, reproduced in
Coping with Methuselah (p. 143). Once AEV is achieved, there will be no
going back: rejuvenation research will be intense forever thereafter and will anticipate
and remedy the life-threatening degenerative changes appearing at newly achieved ages with
ever-increasing efficacy and lead time. This will bring about the greatest economic change
of all in society: the elimination of retirement benefits. Retirement benefits are for
frail people, and there won't
be any frail people. The graph just mentioned amply illustrates how much
wealth will be released by this. My hope, therefore, is that once policy makers begin to
realise what's coming they will factor in this eventual windfall and allocate sufficient
short-term resources to make the period of limited availability of rejuvenation therapies
brief enough to prevent mayhem. This will, however, be possible only if such resources
begin to be set aside long enough in advance—and we don't know how long we have.
