X-Message-Number: 28504
Date: Mon, 25 Sep 2006 19:26:12 -0700 (PDT)
From: Doug Skrecky <>
Subject: aging nematodes undergo mitochondrial degeneration

[Mitochondrial changes may be a major driver of nematode
aging. Whether this is also true of mammals remains an open
question. The causes of mitochondrial changes in nematodes are not well
understood, but transient increases in free radicals may actually help
block these alterations.]

Mech Ageing Dev. 2006 Aug 4; [Epub ahead of print]
Age-related changes of mitochondrial structure and function in
Caenorhabditis elegans.
  A number of observations have been made to examine the role that
mitochrondrial energetics and superoxide anion production play in the
aging of wild-type Caenorhabditis elegans. Ultrastructural analyses
reveal the presence of swollen mitochondria, presumably produced by
fusion events. Two key mitochondrial functions - the activity of two
electron transport chain complexes and oxygen consumption - decreased as
animals aged. Carbonylated proteins, one byproduct of oxidative stress,
accumulated in mitochondria much more than in the cytoplasm. This is
consistent with the notion that mitochondria are the primary source of
endogenous reactive oxygen species. However, the level of mitochondrially
generated superoxide anion did not change significantly during aging,
suggesting that the accumulation of oxidative damage is not due to
excessive production of superoxide anion in geriatric animals. In concert,
these data support the notion that the mitochondrial function is an
important aging determinant in wild-type C. elegans.

Med Hypotheses. 2006;66(4):832-43. Epub 2005 Oct 18.
    Sublethal mitochondrial stress with an attendant stoichiometric
augmentation of reactive oxygen species may precipitate many of the
beneficial alterations in cellular physiology produced by caloric
restriction, intermittent fasting, exercise and dietary phytonutrients:
"mitohormesis" for health and vitality.
    The precise mechanistic sequence producing the beneficial effects on
health and lifespan seen with interventions as diverse as caloric
restriction, intermittent fasting, exercise, and consumption of dietary
phytonutrients is still under active characterization, with large swaths
of the research community kept in relative isolation from one another.
Among the explanatory models capable of assisting in the identification
of precipitating elements responsible for beneficial influences on
physiology seen in these states, the hormesis perspective on biological
systems under stress has yielded considerable insight into likely
evolutionarily consistent organizing principles functioning in all four
conditions. Recent experimental findings provide the tantalizing initial
lodestones for an entirely new research front examining molecular
substrates of stress resistance. In this novel body of research, a
surprising new twist has emerged: Reactive oxygen species, derived from
the mitochondrial electron transport system, may be necessary triggering
elements for a sequence of events that result in benefits ranging from
the transiently cytoprotective to organismal-level longevity. With the
recent appreciation that reactive oxygen species and reactive nitrogen
species function as signaling elements in a interconnected matrix of
signal transduction, the entire basis of many widely accepted theories
of aging that predominated in the past may need to be reconsidered to
facilitate the formulation of an new perspective more correctly informed
by the most contemporaneous experimental findings. This perspective, the
mitohormesis theory, can be used in many disparate domains of inquiry to
potentially explain previous findings, as well as point to new targets
of research. The utility of this perspective for research on aging is
significant, but beyond that this perspective emphasizes the pressing
need to rigorously characterize the specific contribution of the
stoichiometry of reactive oxygen species and reactive nitrogen species
in the various compartments of the cell to cytoprotection and vitality.
Previous findings regarding the influences of free radical chemistry on
cellular physiology may have represented assessments examining the
consequences of isolated elevation of signaling elements within a larger
signal transductive apparatus, rather than definitive characterizations
of the only modality of reactive oxygen species (and reactive nitrogen
species) influence. In applying this perspective, it may be necessary
for the research community, as well as the practicing clinician, to
engender a more sanguine perspective on organelle level physiology, as
it is now plausible that such entities have an evolutionarily
orchestrated capacity to self-regulate that may be pathologically
disturbed by overzealous use of antioxidants, particularly in the
healthy.

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