Aging Cell (2004) 3, pp253254
HEAD-TO-HEAD DEBATE: IS THERE A PROGRAM FOR AGING?
Blackwell Publishing, Ltd.
Rebuttal to Bredesen: The non-existent aging program:
how does it work?
Steven N. Austad
University of Texas Health Science Center, Barshop Center for
Longevity and Aging Studies, San Antonio, TX 78245, USA
In the 1960s, James Hamilton published a series of papers indi-
cating that castration lengthens life in dogs, cats and humans.
Does this indicate that biochemical and molecular pathways
leading to the synthesis of testosterone are part of an aging
program? Most scientists, I would guess, might instead con-
clude that if testosterone is part of any program (something that
is itself highly arguable), it is part of a reproductive program,
where the hormones main Darwinian fitness effects lie, which
is not to say that it might not affect also longevity, as do diet,
physical activity and luck. As I noted in my original article, one
can define phenomena in and out of existence by the breadth
or narrowness of ones definitions. Defining program broadly
enough to encompass how testosterone may affect longevity
strikes me as doing some violence to the normal use of the
word, and also represents something essentially different than
what is generally meant by programming of, say, morphogenesis
by Hox genes or of cell death by apoptosis.
Bredesens claim for a widespread aging program governed
by a longevistat rests, it seems to me, on three considerations:
first, that the inhibition or inactivation of some genes extends
life in model organisms; secondly, that something akin to pro-
grammed cell death seems to occur in a variety of single-celled
organisms, both prokaryotic and eukaryotic; and thirdly, there
exists considerable apparent overlap in the genes involved in
programmed cell death and the modulation of longevity.
One preliminary point to note is that Bredesens focus is
entirely on death rather than aging. Aging is the generalized,
time-dependent decay of phenotypic integrity. Ultimately that
decay leads to death, but one can have lots of decay without
death and death without much decay. The chief focus of aging
theories should therefore probably make predictions about the
nature and rate of decay rather than simply the distribution of
age at death. Unfortunately, in the most facile experimental
model organisms for investigating genetics, we know little
about phenotypic decay (but see Herndon et al., 2002).
Correspondence
Steven N. Austad, University of Texas Health Science Center, STCBM Bldg,
Room 3.100, Barshop Center for Longevity and Aging Studies, 15355 Lambda
Drive, San Antonio, TX 78245, USA. Tel.: +1 210 562 6011;
e-mail: austad@uthscsa.edu
Accepted for publication 19 July 2004
Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2004
Doi: 10.1111/j.1474-9728.2004.00119.
That the inhibition or inactivation of a variety of genes
extends life under laboratory conditions is well established and
non-controversial in model yeast, nematodes, flies, and mice.
What this suggests about the existence of an aging program is
another matter. Clearly the genes involved in major biochemical
pathways are organized into integrated, hierarchical pathways.
However, if altering a component of those pathways influences
by some unknown mechanism(s) some measure of disorgan-
ization and decay much later on, that seems to me substantially
different than apoptosis in which steps in the causal chain from
receptor activation to effector activation are understood. As
regards timing of death, even in the best understood organism,
we have no clue as to what the effectors might be. We know
that x activates y, let us say, which activates (or inhibits) a, b
and z, at which point a-whole-lot-of-stuff-happens, which then
influences the timing of death, weeks or months or years later.
In fact, we cannot predict in particular cases if it will be days,
or weeks or months later. Some daf-2 mutants of C. elegans,
for instance, may die at 10 days of age, some at 50 days. Given
this amount of uncertainty as to the outcome, it is not obvious
to me how that represents some sort of program any more than
the longevity effects of altering testosterone or dietary fat avail-
ability can be said to indicate programmed longevity. Assuming
that a program is most usefully thought of as a stereotyped
sequence of events leading to an intended outcome, then there
is little reason to imagine that even though alterations in gene
expression in early life ultimately change the pattern of death
very much later on, that this represents a program. There is nei-
ther the intended outcome as moulded by natural selection nor
the stereotypy. Aging, even in the case of genetically identical
organisms living in a homogeneous soup, is characterized by
phenotypic variation and loss of regulation of gene expression
and protein turnover (Finch & Kirkwood, 2000; Herndon et al.,
2002). A collateral question is whether it matters what the
genes (alleles) are there for or whether as Bredesen suggests
this is more a philosophical than scientific issue. Actually what
the genes are there for is easily understood and makes a great
deal of scientific difference. They are there because they confer
fitness advantages in the environment in which they evolved.
Therefore, it is functionally significant and not the least surpris-
ing to evolutionary biologists that direct competition under
reasonably realistic conditions between wild-type animals and
longevous mutants such as age-1 or daf-2 in C. elegans is rap-
idly resolved in favour of the wild-type (Walker et al., 2000; N.
L. Jenkins, G. McColl & G. J. Lithgow, pers. comm. 2004).
It is certainly intriguing that a number of single-celled organ-
isms can undergo something akin to programmed cell death,
253
254 Is there a program for aging?, S. N. Austad
which in their case is equivalent to programmed organismal
death. Of course, programmed death of whole organisms is well
known, widespread (plants to octopuses to salmon to marsu-
pials) and easily reconciled with evolutionary senescence theory,
sometimes invoking group selection, sometimes not. Group
selection clearly occurs in nature. It just is not virtually ubiquitous
as is aging. Group selection simply requires specific conditions
to be more powerful than individual selection. It is most power-
ful when groups behave like individuals. That is, they share a
high degree of genetic relatedness, mix little with individuals
more distantly related to them, and the actions of individuals
affect the reproductive success of the group. The extreme case
is multicellular organisms themselves, in which the evolutionary
fate of individual cells is linked to whether they contribute to
keeping the whole organism alive and reproducing, not whether
they reproduce themselves. Cells that misbehave, reproducing
when they should not for instance, cause cancer and soon reach
an evolutionary dead-end.
Among single-celled organisms, one can imagine many
scenarios in which these conditions would be met, because
reproduction is predominantly asexual, seeming to favour large
contiguous populations of genetically identical individuals. The
extent to which the evolutionary fate of these individuals is
linked will depend on the species ecology. For instance, in one
well-described case cited by Bredesen, Leishmania, the single-
celled parasitic protozoan that causes several disease forms
called leishmaniasis exhibits programmed cell death. The para-
site is transmitted from mammals to sand flies when the flies
bite an infected host. It is also transmitted from sand flies to
mammals when an infected insect bites an uninfected host. Evo-
lutionary success in this case is the number of new hosts infected.
Because the transmission probability between insect and mammal
or vice versa, as well as the pathogenicity to the host, is likely to
depend on parasite population density within hosts, a scenario
in which strict group limits on population size within the host,
potentially mediated by programmed parasite death, may be
essential for evolutionary success of the parasite genome itself.
Finally, Bredesen makes the fascinating observation that a
number of the same genes involved in modulating programmed
cell death also seem to be involved in modulating longevity.
There are, however, other explanations for this observation
than suggesting an organismic aging program analogous to
Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2004
programmed cell death. Most intriguingly, Promislows (2004)
recent work on protein networks and replicative senescence in
yeast found that proteins involved in senescence were both
highly pleiotropic (affect many biological functions) and inter-
acted with unexpectedly high numbers of other proteins com-
pared with proteins involved in other cellular functions. My
subjective impression given the complexity of the pathways is
that proteins involved in programmed cell death may also be
involved in exceptionally high numbers of protein interactions.
Thus the number of proteins common to senescence and pro-
grammed cell death may be less surprising than it first appears.
In summary, evolutionary biologists claim that aging is not
generally programmed does not rest on theory alone as Bredesen
suggests. It also rests on observations. Two of these are that
the aging phenotype as well as age-at-death are highly variable
and occur by no known stereotypical process even within genet-
ically identical individuals reared and maintained in identical
environments, and that the well-known instances of programmed
organismic death as represented by salmon differ substantially
from the type of death seen among other organisms.
It is not surprising that biologists who focus their research
on genetic or signal transduction pathways should develop a
worldview that emphasizes stereotyped, sequential processes.
Indeed, it is now clear that such processes contribute to aging
in many animals. It is equally clear to me that calling such con-
tributions a program misleads us about the essential nature of
aging, which is increasing decay and an attendant loss of reg-
ulation. The field of biogerontology will only gain, however,
from a continuing dialogue among biologists from a variety of
worldviews.
References
Finch CE, Kirkwood TRL (2000) Chance, Development, and Aging. New
York: Oxford University Press.
Herndon LA, Schmeissner PJ, Dudaronek JM, Brown PA, Listner KM,
Sakana Y, Paupard MC, Hall DH, Driscoll M (2002) Stochastic and
genetic factors influence tissue-specific decline in ageing C. elegans.
Nature 419, 808814.
Promislow DEL (2004) Protein networks, pleitropy and the evolution of
senescence. Proc. R. Soc. Lond. B Biol. Sci. 271, 12251234.
Walker DW, McColl G, Jenkins NL, Harris H, Lithgow GJ (2000) Natural
selection: evolution of lifespan in C. elegans. Nature 405, 296297.