X-Message-Number: 25677
Date: Thu, 10 Feb 2005 20:24:07 -0800 (PST)
From: Doug Skrecky <>
Subject: free radical theory of aging generalized

[This "green" theory now adds phase 1 and phase 2 detoxification
pathways to traditional free radical protective mechanisms. There might
be something to this, since these pathways are associated with variations
in cancer risk in humans. However there is no proof yet that these can
modulate human maximum lifespan.]

Mech Ageing Dev. 2005 Mar;126(3):381-7.
Broad spectrum detoxification: the major longevity assurance process
regulated by insulin/IGF-1 signaling?
  Our recent survey of genes regulated by insulin/IGF-1 signaling (IIS) in
Caenorhabditis elegans suggests a role for a number of gene classes in
longevity assurance. Based on these findings, we propose a model for the
biochemistry of longevity assurance and ageing, which is as follows.
Ageing results from molecular damage from highly diverse endobiotic
toxins. These are stochastic by-products of diverse metabolic processes,
of which reactive oxygen species (ROS) are likely to be only one
component. Our microarray analysis suggests a major role in longevity
assurance of the phase 1, phase 2 detoxification system involving
cytochrome P450 (CYP), short-chain dehydrogenase/reductase (SDR) and
UDP-glucuronosyltransferase (UGT) enzymes. Unlike superoxide and hydrogen
peroxide detoxification, this system is energetically costly, and
requires the excretion from the cell of its products. Given such costs,
its activity may be selected against, as predicted by the disposable soma
theory. CYP and UGT enzymes target lipophilic molecular species;
insufficient activity of this system is consistent with age-pigment
(lipofuscin) accumulation during ageing. We suggest that IIS-regulated
longevity assurance involves: (a) energetically costly detoxification and
excretion of molecular rubbish, and (b) conservation of existing proteins
via molecular chaperones. Given the emphasis in this theory on investment
in cellular waste disposal, and on protein conservation, we have dubbed
it the green theory.

J Biol Chem. 2004 Oct 22;279(43):44533-43. Epub 2004 Aug 11.
Shared transcriptional signature in Caenorhabditis elegans Dauer larvae
and long-lived daf-2 mutants implicates detoxification system in
longevity assurance.
  In the nematode Caenorhabditis elegans, formation of the long-lived
dauer larva and adult aging are both controlled by insulin/insulin-like
growth factor-1 signaling. Potentially, increased adult life span in
daf-2 insulin/insulin-like growth factor-1 receptor mutants results from
mis-expression in the adult of a dauer larva longevity program. By using
oligonucleotide microarray analysis, we identified a dauer transcriptional
signature in daf-2 mutant adults. By means of a nonbiased statistical
approach, we identified gene classes whose expression is altered
similarly in dauers and daf-2 mutants, which represent potential
determinants of life span. These include known determinants of longevity;
the small heat shock protein/alpha-crystallins are up-regulated in both
milieus. The cytochrome P450, short-chain dehydrogenase/reductase,
UDP-glucuronosyltransferase, and glutathione S-transferase (in daf-2
mutants) gene classes were also up-regulated. These four gene classes act
together in metabolism and excretion of toxic endobiotic and xenobiotic
metabolites. This suggests that diverse toxic lipophilic and
electrophilic metabolites, disposed of by phase 1 and phase 2 drug
metabolism, may be the major determinants of the molecular damage that
causes aging. In addition, we observed down-regulation of genes linked to
nutrient uptake, including nhx-2 and pep-2. These work together in the
uptake of dipeptides in the intestine, implying dietary restriction in
daf-2 mutants. Some gene groups up-regulated in dauers and/or daf-2 were
enriched for certain promoter elements as follows: the daf-16-binding
element, the heat shock-response element, the heat shock-associated
sequence, or the hif-1-response element. By contrast, the
daf-16-associated element was enriched in genes down-regulated in dauers
and daf-2 mutants. Thus, particular promoter elements appear
longevity-associated or aging associated.

Mutat Res. 1989 Mar;219(2):89-94
P1-450 and P3-450 gene expression and maximum life span in mice.
  The effects of beta-naphthoflavone on the inducibility of hepatic P1-450
and P3-450 mRNA were investigated in male B10.RIII/Sn, C57BL/10Sn,
C3H/HeSnJ, and A/WYSn mice. Previous work has shown that the maximum
level of aryl hydrocarbon hydroxylase induction in these strains
correlates with maximum life span. In this study we found that the maximum
inducible levels of P1- and P3-450 RNA were significantly different among
the strains, and these levels also correlate with life span. The
differences were not due to strain-specific differences in the kinetics
of P1- or P3-450 RNA induction. The differences were specific to
expression of the P-450 genes, since the levels of hepatic alpha-actin
and albumin RNA were not significantly different among the strains, and
specific RNA levels were normalized to the level of total polyadenylated
RNA. beta-Naphthoflavone was found to induce alpha-actin mRNA
approximately 2-fold and to transiently repress albumin RNA about 50% in
all mouse strains. Maximum P1- and P3-450 gene expression correlated
directly with the 10th deciles of survival of the mouse strains.
Longer-lived strains expressed higher combined levels of P1- and P3-450
RNAs. Maximum P1- and P3-450 gene expression also correlated generally
with the reported aryl hydrocarbon hydroxylase receptor levels of each
strain. It is unlikely that the hepatic P1- and P3-450 genes are ever
maximally induced under the sheltered laboratory conditions used to
determine maximum life span, as we consistently find very low levels of
P-450 expression in uninduced animals. These uninduced levels were not
statistically different between the strains. Therefore, the reason for
the relationship between maximum life span and maximum P1- and P3-450
inducibility is unclear at present.

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