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Chapter 11
Evolutionary Nutrigenomics
Michael R. Rose, Anthony D. Long, Laurence D. Mueller, Cristina L. Rizza,
Kennedy C. Matsagas, Lee F. Greer, and Bryant Villeponteau
Contents
11.1 Introduction: Aging Arises from a Failure of Adaptation, Not Cumulative Damage 357
11.2 Making SENSE: Strategies for Engineering Negligible Senescence Evolutionarily 358
11.3 Using Double-Screen Genomics to Identify Targets for Intervention ....... 359
11.4 Pharmaceutical Versus Nutritional Intervention Strategies ........... 360
11.5 Genescient Uses Two Key Accelerators to Identify Evolutionary
Nutrigenomic Agents ............................ 362
11.6 Genescient Progress Report ......................... 363
11.7 Conclusions: Prospects for Evolutionary Nutrigenomics ............ 364
References ................................... 365
11.1 Introduction: Aging Arises from a Failure of Adaptation,
Not Cumulative Damage
The common assumption among gerontologists is that aging is a process of inex-
orably accumulating damage or disharmony. This assumption has held sway since
Aristotle, the chief source of variation in the articulation of this assumption being
the historically prevalent fashions in biological thought, from the four Greek ele-
ments of air, fire, water, and earth to contemporaneous notions about oxidation, free
radicals, and the like (Rose 2007). The falsity of this assumption is revealed by three
obdurate biological facts:
(i) there are organisms like fissile sea anemones and Hydra which show no
detectable aging;
(ii) species are sustained by unbroken cell lineages that are hundreds of millions
of years old, whether those lineages engage in sex or not; and
M.R. Rose (B)
Genescient, LLC, Irvine, CA, USA
e-mail: mrose@genescient.com
357
G.M. Fahy et al. (eds.), The Future of Aging, DOI 10.1007/978-90-481-3999-6_11,
C
Springer Science+Business Media B.V. 2010
358 M.R. Rose et al.
(iii) in some laboratory cohorts of sufficient size, actuarial aging comes to a halt at
late adult ages (Rose 2008).
None of these now well-established features of aging are compatible with the
view that aging is simply and solely a result of inexorably accumulating damage,
disharmony, or the like.
Instead, aging is due to sustained declines in Hamilton’s Forces of Natural
Selection (Hamilton 1966; Charlesworth 1980;Rose1991;Roseetal.2007).
Natural selection is what produces adaptation, the term “adaptation” referring to
attributes useful for survival and reproduction. As the power of natural selection
declines, a decline that Hamilton’s Forces quantify explicitly and from first princi-
ples, adaptation is expected to decline. This is how evolutionary biologists explain
aging.
Cases in which aging does not occur at all, such as strictly and symmetrically
fissile species or evolving germ lines, are instances where Hamilton’s Forces do not
decline at any point. Notably, it has recently been shown that the apparent cessation
of aging late in adult life is also explicable in terms of Hamilton’s Forces (Mueller
and Rose 1996; Rose et al. 2002; Rauser et al. 2006). That is, there is a direct cor-
respondence between situations in which aging is not observed and circumstances
in which Hamilton’s Forces do not decline. This is one of many types of empirical
evidence that support the Hamiltonian explanation of aging (Rose 1991;Roseetal.
2007). Significantly for Popperian scientists, there are no well-attested refutations of
the Hamiltonian theory of aging. This is a significant advantage of the Hamiltonian
theory of aging for evolutionary geneticists, physicists, and other scientists who
practice “strong inference” (vid. Platt 1964).
Naturally enough, evolutionary biologists have been able to readily and substan-
tially postpone aging by manipulating Hamilton’s Forces (Rose and Charlesworth
1980; Luckinbill et al. 1984;Rose1991), a track record that is unmatched
by attempts to manipulate aging based on non-evolutionary gerontological the-
ories. This is not surprising, because most mainstream gerontological theories
are variants of Aristotle’s original error about aging. Our conclusion is that
the Hamiltonian gerontology provides the best scientific foundation for properly
thought-out attempts to substantially intervene in the process of aging (Rose 1991,
2008).
11.2 Making SENSE: Strategies for Engineering Negligible
Senescence Evolutionarily
In this article, we principally address this question of how to use Hamilton’s Forces
to ameliorate human aging. This is a question that we have long pursued (e.g. Rose
1984,2005,2008), generally without making any material headway. There was a
singular reason for this past failure: evolutionary biologists had not been given the
resources to pursue any of their proposals as to how we might ameliorate aging in
11 Evolutionary Nutrigenomics 359
humans, despite their notable successes both at explaining aging scientifically and
at slowing aging in laboratory populations. We will not comment here on why this
regrettable situation was allowed to subsist, and turn instead to recent developments
that have proven surprisingly positive.
We have recently summarized alternative strategies for engineering negligible
senescence based on the scientific foundations supplied by evolutionary biology
(“SENSE”), rather than the typical foundations supplied by current fashions in cell
and molecular gerontology (Rose 2008). These SENSE strategies are based on using
Hamilton’s Forces to produce model organisms with slowed aging and then reverse-
engineering the biology of those organisms to discover interventions that can be
used to ameliorate human aging.
The chief issue within Hamiltonian gerontology has been the best type of organ-
ism to use in this project. In the 1980s, it was supposed that only a mammalian
species would yield Hamiltonian results that could be reliably reverse-engineered
(e.g. Rose 1984), because of the close evolutionary relationship among mammalian
species and the then-considerable difficulty of discerning genetic commonalities
between humans and less-related species, such as insects and nematodes. But with
the advent of powerful genomic technologies circa the year 2000, it became appar-
ent that it might be possible to use fruit flies that had been forced to evolve slower
aging using Hamiltonian methods (Rose et al. 2004), the so-called “Methuselah
Flies,” as an alternative to mice, so long as “SENSE Methuselah Mice” were not
available (Rose 2008). Thus the most immediate prospect for SENSE is the use of
Hamiltonian, or SENSE, Methuselah Flies as a source of genomic information with
which to develop useful ways to ameliorate human aging. It is this prospect which
is our chief concern here.
11.3 Using Double-Screen Genomics to Identify Targets
for Intervention
With the whole-genome sequencing of both humans and fruit flies circa 2000, as
well as the concomitant advent of whole-genome tools for measuring gene expres-
sion, there is now an “information superhighway” connecting fruit flies and humans.
It is now trivial to identify corresponding genes (“orthologs”) between these species.
Furthermore, it is easy to compare genetic and gene-expression differences between
Methuselah Flies produced using Hamiltonian methods with their matched controls.
In 2006, Genescient LLC took advantage of these technologies to compare
whole-genome gene-expression patterns in Methuselah Flies with their matched
controls. We found about 1,000 genes showing statistically significant differences in
expression. These genes are thus presumptive candidates for the genetic changes that
underlie the substantially ameliorated aging achieved using Hamiltonian methods in
fruit flies. Even more exciting for the purpose of reverse-engineering interventions,
in 2007 we found that more than 700 of these genes had matching “orthologous”
loci in the human genome.
360 M.R. Rose et al.
Fig. 11.1 Genescient
identified human aging genes.
Compared low and high risk
patients with chronic diseases
to wild-type and long-lived
flies to obtain orthologs
relatedtoaging
Fig. 11.2 Genetic overlap
identifies shared aging
pathways. Overlap of
Drosophila longevity genes
and human disease genes
generating greater health risks
The second phase of our work was to use extant human genome-wide association
studies (GWAS) to ascertain whether any of these orthologous loci were statistically
associated with reduced risks of aging-associated disease. So far, we have more than
100 human genes showing such statistical associations with risks of contracting such
diseases. These genes thus became Genescient’s targets for intervention.
Figures 11.1 and 11.2 give a crude graphical outline of the two basic genomic
screens that we have performed, searching for genomic changes that are associated
with increased lifespan in Drosophila as well as better chronic disease outcomes in
human subjects.
11.4 Pharmaceutical Versus Nutritional Intervention Strategies
So long as one supposes that aging is due to just a few “master regulatory” genes
(e.g. Guarente and Kenyon 2000) or a handful of fully delimited types of accu-
mulating damage (e.g. de Grey and Rae 2007), then it is reasonable to suppose
11 Evolutionary Nutrigenomics 361
that massively effective “anti-aging” pharmaceuticals might be discovered. In other
words, so long as aging is NOT conceived in Hamiltonian terms, then anti-aging
pharmaceuticals should be possible, despite the failure of all attempts to produce
any such agents throughout the lengthy history of the many attempts to do exactly
that.
But on the Hamiltonian view of aging, and given Genescient’s own genomic
results described above, it is only to be expected that aging involves a failure of
natural selection across hundreds of genes, with many physiological mechanisms of
aging produced by these failures of adaptation. The prospects for developing FDA-
approvable pharmaceuticals for such a “Many-Headed Monster” as aging (cf. Rose
and Long 2002) are extremely doubtful, if not hopeless. But does this mean that
there are no prospects for ameliorating human aging? We don’t think so.
Understanding how natural selection creates adaptations is the key to understand-
ing Genescient’s evolutionary nutrigenomic strategy. There are a few cases (such as
those involving short-term selection for resistance to antibiotics, heavy metals, or
pesticides) where natural selection produces adaptations based on single genetic
changes. But when the genetic basis of typical adaptations is studied, adaptations
such as body size or resistance to cancer, it is commonly found that many genes
underlie these adaptations. Thus it is no surprise to evolutionary geneticists that
the genetic basis of the several-fold extension of Methuselah Fly lifespans involves
hundreds of genes. To re-shape aging, we will need to make appropriate adjustments
involving many biochemical pathways.
At this point, a reader of the gerontological literature might point to the
“longevity mutants” that have been such an obsession in recent gerontological
research (reviewed in Guarente and Kenyon 2000,aswellasArking2006). Such
“longevity” mutations have been known for more than fifty years (e.g. Maynard
Smith 1958). When they are studied with greater and greater care for their side-
effects, which has not always been standard practice within the gerontological
research community, they are characteristically found to show debilitating effects on
fitness, reproduction, and related functions (Van Voorhies et al. 2006). The pathways
that are “knocked-out” by these “longevity mutants” typically produce extended
lifespan in a manner that is achieved at great physiological cost, such as sterility,
dwarfism, or metabolic hibernation. Such side-effects make these “longevity genes”
unlikely targets for the extension of “human healthspan,” although they might be
useful targets for preserving the lives of hospitalized patients under extreme med-
ical conditions, in which reproductive incapacitation or impaired cognition might
not be issues.
To return to the Hamiltonian perspective, the technological problem is evidently
one of re-tuning hundreds of genetically-defined mechanisms of aging. This prob-
lem is readily solved by natural selection, as the Hamiltonian Methuselah Flies
directly demonstrate. Furthermore, we know from detailed studies of individual loci
in these flies that these manifold re-tunings do not involve “knocking-out” or other-
wise destroying normal genetic mechanisms (Rose et al. 2004; Teotonio et al. 2009).
Instead, as Genescient’s own genomic findings show in great detail, the evolutionary
changes that lead to greatly slowed aging involve relatively subtle changes in gene
362 M.R. Rose et al.
frequency and gene expression, in most cases. Such subtle changes are not effects
that pharmaceuticals notably emulate.
Instead, the best strategy for emulating the effects of natural selection in extend-
ing lifespan several-fold is nutritional supplementation. This does NOT mean
ingesting large quantities of hundreds of supplements that one or another molec-
ular biologist supposes might be beneficial based on results obtained using in vitro
cell cultures. Indeed, the wholesale failure of such research to produce extended
human healthspans suggests the greatest caution in using guidelines derived from
such work.
The Hamiltonian perspective suggests instead using nutritional supplements in
the same manner as evolution uses genetic variants of small effect. Genetic changes
that do not have massively disruptive effects, unlike the “longevity mutants,” are
likely to alter a number of physiological mechanisms a small amount. Similarly,
nutritional supplements that do not have drastic effects are likely to have moderate
effects on a number of physiological mechanisms. This does NOT, however, mean
that these effects are on the whole benign. Just that they are moderate.
In Hamiltonian experiments in which we evolve postponed aging in model
animal species, natural selection “screens” such moderate, often diffuse, genetic
effects, favoring those variants that have benign effects accumulated over the
entire spectrum of physiological functions. Likewise, we have to screen candi-
date “nutrigenomic agents” for their benefits, just as natural selection would. Just
because a nutritional supplement seems like it should be beneficial based on our
genomic findings is no guarantee that it will in fact be useful in the amelioration of
human aging.
11.5 Genescient Uses Two Key Accelerators to Identify
Evolutionary Nutrigenomic Agents
Genescient’s evolutionary nutrigenomic approach is based on emulating natural
selection, using nutritional supplements in lieu of genetic variation, with two major
“accelerators,” as follows:
Accelerator 1: We choose candidate substances based on biochemical associa-
tions between the effects of candidate substances and the pathways that Genescient
has identified genomically. Mutation supplies “blind variation” for natural selection
to act on. While we are very far from supposing that contemporary biochem-
istry is infallible, the physiological mechanisms and gene products disclosed by
Genescient’s Hamiltonian genomics provide valuable clues that can be combined
with the published literature and small-molecule databases to direct us toward some
nutritional supplement choices over others. Thus, our first accelerator lets us do even
better than natural selection, by using our proprietary genomic insights combined
with extant biochemical information.
Accelerator 2: We first test our candidate nutrigenomic agents using fruit fly
healthspan assays, followed by human functional tests. Since we operate within
the Hamiltonian paradigm, we are not interested in substances that might increase
longevity at great functional cost. Instead, we are interested in supplements that will
11 Evolutionary Nutrigenomics 363
enhance longevity, fertility, cognitive function, physical performance, et cetera,all
at the same time. This means that we seek substances that can be shown to have
both long-term and short-term benefits.
In principle, all our developmental research could be performed on human sub-
jects. But to seek measurable benefits for human healthspan, when we expect such
benefits to be of small magnitude for any single supplement, is commercially hope-
less. We would never get access to the funding required to test dozens, not to say
eventually hundreds, of candidate nutritional supplements over large test groups
of human subjects over decades, prior to marketing the compounded nutrigenomic
agents as commercial products.
This is where the evolutionary foundations of our nutrigenomic strategy pay par-
ticularly large dividends. All the genetic mechanisms targeted by our nutrigenomic
candidate substances have been implicated in both fruit flies and humans. If we
have an excellent nutritional supplement based appropriately on genes that are asso-
ciated with healthspan in both fruit flies and humans, it should benefit both fruit
flies and human subjects. We can readily screen for lifelong benefits in fruit flies.
Genescient scientists have decades of expertise in accurately and efficiently char-
acterizing longevity, mortality rates, fecundity, male mating success, and related
lifelong indicators of healthspan in fruit flies. We can also readily screen for useful,
short-term, functional benefits in humans, because there is no other organism for
which we have better metrics for short-term function. Naturally enough, we start
with fruit fly tests, passing candidate nutrigenomic agents on to human testing only
once we have cleared them for lifelong benefits in fruit flies. Figure 11.3 summarizes
this R&D strategy.
11.6 Genescient Progress Report
It might be useful to summarize Genescient’s progress to date in broad terms. [We
are in the process of writing up and submitting detailed “data papers” for publica-
tion in the scientific literature.] That way the reader will have a more concrete idea
Fig. 11.3 Shared aging
genes are used to develop
nutrigenomic treatments.
Substances (δ’s) are identified
that act on human disease
pathways and then are tested
in fly aging assays. Lead hits
that extend fly healthspan are
screened in humans for
enhanced function
364 M.R. Rose et al.
of what Genescient has accomplished, by way of materially embodying its R&D
strategy.
1. We have already performed an extensive genomic inventory of the gene-
expression changes that underlie the several-fold extension of lifespan in
Hamiltonian Methuselah Flies. We have found about 1,000 genes for which there
are statistically significant and consistent changes in gene expression that result
from selection for increased adaptation at later ages, including survival to, and
function at, much later ages than is normal for laboratory fruit flies.
2. We have used GWAS databases to identify more than 100 genetic loci that are
associated with both increased fly lifespan and decreased risk of chronic human
diseases, such as cardiovascular and metabolic disorders.
3. We have used the key loci identified in step 2 to choose nutritional supplements
that we regard as candidates for nutrigenomic agents that might give enhanced
healthspan in both humans and fruit flies.
4. One significant result from this initial screen is that high doses were often less
effective than low or moderate doses. Therefore, more of a longevity compound
is not necessarily better.
We are now performing trials to test for the effects of combinations of nutrige-
nomic agents that have passed through our R&D program. We also plan human
trials to test for short-term functional effects of our candidate nutrigenomic agents.
Following the completion of these tests, we would like to produce nutrigenomic
products for sale in the marketplace.
11.7 Conclusions: Prospects for Evolutionary Nutrigenomics
Genescient’s evolutionary nutrigenomic R&D strategy is expandable in many direc-
tions, and on a very large scale. Here are several ways we can build on what we have
accomplished to this point.
1. The genomic work we have done to this point with the Hamiltonian Methuselah
Flies is just a start. New genomic technologies are being released rapidly, from
tiling arrays to large-scale rapid re-sequencing. The use of any and all of these
technologies will reveal still more detail concerning the genomic foundations of
the Hamiltonian prolongation of healthspan.
2. Likewise, human population genomics is a rapidly burgeoning field. As more
human genomic data become available, we will find still more genes that are key
for aging in both fruit flies and humans.
3. Given enough resources, we can select on mice using Hamiltonian strategies, as
originally proposed 25 years ago. Such mice would provide still more genomic
information concerning the genetic controls on human aging.
11 Evolutionary Nutrigenomics 365
4. Small-molecule databases are rapidly improving, thanks to the application of
high-throughput methods for detecting interactions between individual gene-
products and candidate small molecules. These databases will furnish more
candidates for testing as potential nutrigenomic agents.
5. We look forward to the development of better, and more widely-accepted,
protocols for testing human functions, whether cognitive, athletic, or metabolic.
There is nothing easy or magical about the Hamiltonian approach to the amelio-
ration of human aging. But it may well be the best strategy for radical extension of
human healthspan that is both scientifically well-founded and experimentally sup-
ported. We regard the alternatives as more challenging, however widely accepted
within conventional gerontology or geriatrics. As we have said before (Rose 2008),
the difficulty of materially extending useful healthspan helps reveal which of the
contending scientific and technological approaches to aging are well-founded, and
which are not.
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