X-Message-Number: 8286
From: Brian Rowley <>
Subject: Life Extension Supplements: Screens on Lower Organisms
Date: Thu, 5 Jun 1997 22:40:27 -0700

What follows are arguments in favor of screening life extension supplements
on lower organisms (e.g., fruit flies, rotifers and nematodes), and ideas
for carrying out such screens.

MORTALITY STUDY SHORTAGE

        There are countless drugs which *might* delay mortality, but which
no one has tested for mortality effects. Doug Skrecky dug up all
Medline-accessible fruit fly mortality studies where anti-aging drugs were
screened since 1966 and the result was a pile no taller than an inch. The
rodent mortality study literature is equally scant. The fact is, not many
scientists want to bother with mortality studies because they (a) take a
long time and are therefore slow to publish (b) are expensive and (c) are
about aging (criticism and cynicism about life extension). Most drug
companies are similarly not interested in mortality studies, although they
test their drugs for long term toxicity. We're at a stage where the chemists
and molecular biologists have grossly outstripped the gerontologists. We've
got an array of exciting drugs and hormones to test which might extend the
life span, but few pharmacologists who will test them. Take DHEA and even
many vitamins, for example--much excitement, no reliable mortality data
(however Richard Weindruch at the Univ. of Wisconsin at Madison is now doing
a proper DHEA mortality study).

MULTI-DOSE TRIALS

        What mortality data exists is almost entirely from one-dose
experiments. For example, melatonin mortality studies I've seen test only
one dose of melatonin. My training in pharmacology (an MS) has led me to
believe that many doses should be tried in drug trials. One wants to know
(1) what is the maximum achievable effect of the drug (efficacy), (2) how
much of the drug do you have to take for an effect (potency) and (3) how
much of the drug is too much (toxicity). Only multiple dose screens give you
this information. Another reason to test multiple drug concentrations is
that drugs bind to totally different receptors (and have totally different
effects) at different doses. At low doses, vasopressin is a brain peptide
that influences cognition. At higher doses, it is a brain peptide
influencing cognition that also acts as an anti-diuretic hormone. At even
higher doses, its action as a brain peptide changes, it has an anti-diuretic
effect and now also raises the blood pressure. A one-dose drug trial for
vasopressin, as for all other drugs, would be virtually meaningless. One
answer is to test anti-aging drugs on lower organisms, which would allow
more drugs to be tested at more dose levels, faster, cheaper and with
greater sample sizes.

COMBINATIONS OF ANTI-AGING DRUGS

        Multi-dose screens for life extension drugs are rare enough. Rarer
still are *combination* drug screens, which would reveal synergistic effects
between different agents. If the process of aging is multifactorial, a
series of interventions might be necessary. The ultimate aim is to develop
an optimized "cocktail" of agents, each ingredient acting synergistically.
If 5 mg of drug A increases life span by 10%, and 5 mg of drug B increases
life span by 10%, by how much will 5 mg of *both* drugs increase life span?
Possibly by more than 10%, unless the drugs have bad interactions or work by
the same mechanism. Of course, before testing drugs in combination, one
first needs to establish that both agents have an effect, and the dosages
needed for optimal effect should first be determined.

SCREENING LIFE EXTENSION SUPPLEMENTS ON LOWER ORGANISMS

        Can the use of lower organisms (e.g., fruit flies) be justified?
After all, the goal is to slow mammalian aging, not fruit fly aging. Fruit
flies don't die of the same causes as humans, just as paramecia don't die of
the same causes as fruit flies. Nonetheless, even these 3 seemingly
unrelated species are related metabolically; fruit flies, humans and
paramecia share a number of key enzymes, including cytochrome c and other
respiratory chain enzymes, ATP synthetase enzymes, superoxide dismutase
(SOD)... In fact, fruit flies, humans and paramecia share basic longevity
assurance mechanisms: all have antioxidant defense enzymes, DNA repair
enzymes... Fruit flies and lower organisms have similarities to mammals at
the metabolic, if not gross level, so there is some theoretical
justification in screening anti-aging drugs on lower organisms.

        There is also empirical justification: treatments which delay
mortality in lower animals often delay mortality in higher animals. For
example, melatonin delays mortality in rotifers, as well as mice. Mice are
mammals while rotifers are microorganisms not even made up of separate cells
(they're just teensy columns of polynucleated protoplasm). Do rotifers die
of the same causes as mice? Apparently not, as mice die of cancer, kidney
disease, vascular disease... none of which affect rotifers. Yet the effect
of melatonin on rotifer mortality successfully predicts a similar effect in
mice. If a scientist tested melatonin on rotifers as a preliminary screen
for a subsequent mouse trial, he would not be misled by the result.

        Another example: Caloric restriction delays mortality in paramecia,
rotifers, daphnia (a fresh-water shellfish 2-3 millimeters long), spiders,
fish, mice, rats, and (I think) guinea pigs. Yet it cannot be said that
paramecia, rotifers, daphnia or spiders die from the same causes as rats. At
least, not if one defines cause of death anthropocentrically using end-stage
outcome terms like "heart attack, cancer, stroke...", instead of a more
general phrase like, "progressive malfunction of life maintenance processes
common to all species leading to weakening at the molecular level which
increases susceptibility to a variety of stochastic disease processes". The
effect of caloric restriction on the mortality of paramecia, rotifers,
daphnia and spiders predicts a similar effect on mouse mortality--that's
evidence in favor of using lower organisms as screens for anti-aging
treatments, and also suggests some commonalities of aging mechanisms across
phylogenies.

        There are exceptions: caloric restriction does not delay mortality
in amoeba or fruit flies, so it only works on 8/10 of the species I know
about. Still, what delays mortality in a lower organism delays mortality in
a mammal often enough to justify using lower organisms as screens, and often
enough to propose the existence of common mechanisms of aging that span
phylogenies.

        The accuracy of lower organismal data, in terms of predictive power
for longevity effects in rodents, surely goes up the more species of lower
organism you use to do screens. For example, if an anti-aging supplement
extends the life span of rotifers I would be interested. However, if the
same supplement could be shown to also extend the life span of nematodes and
fruit flies, I would be very, very interested. In fact, I would want to try
it out on long-lived strains of mice as a fair bet.

        I've dreamt of creating an "invention factory" for life extension
drugs, where supplements are screened at multiple doses with high sample
sizes, first alone and then in (hopefully synergistic) combinations. Such
rigorous, exhaustive screens would be possible using lower organisms;
mortality data from rotifers is obtainable within a week, data from
nematodes is obtainable within a month, data from fruit flies is obtainable
within 2 months... the winning drug combinations, effective in more than one
lower organism, could then be tested on long-lived strains of rodents.

        Soon I will post an outline of Materials and Procedures for some
supplement screens I'll be doing this summer, during which time I will test
5-6 dose doublings of pikamilone (nicotinoyl-GABA), melatonin,
centrophenoxine and other supplements in search of anti-aging effects. I owe
many thanks to Doug Skrecky whose idea it was to do fruit fly screens in
general, and whose experience and impeccable reading of the literature have
given me some great insights. I also give big thanks to Dr. Robert Ettinger,
who has agreed to fund the research.

Brian Rowley

P.S. Stephen Spindler's lab (where I will be doing my Ph.D. starting this
September) is also testing supplements for anti-aging effects, probably
including in vitro work. Life doesn't get much more exciting than this for a
life extension fanatic :->

Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=8286