X-Message-Number: 26132
Date: Wed, 4 May 2005 19:45:53 -0700 (PDT)
From: Doug Skrecky <>
Subject: Testing the "garbage" accumulation theory of ageing

Biogerontology. 2005;6(1):39-47.
Testing the "garbage" accumulation theory of ageing: mitotic
activity protects cells from death induced by inhibition of autophagy.
Stroikin Y, Dalen H, Brunk UT, Terman A.
  Imperfect autophagic degradation of oxidatively damaged
macromolecules and organelles (so-called biological "garbage") is
considered an important contributor to ageing and consequent death
of postmitotic (non-dividing) cells, such as neurons and cardiac
myocytes. In contrast, proliferating cells apparently escape
senescence by a continuous dilution and repair of damaged structures
during division. Postmitotic ageing can be mimicked and studied in
cultures of potentially dividing cells if their mitotic activity is
inhibited. To test the "garbage accumulation" theory of ageing, we
compared survival of density-dependent growth-arrested (confluent)
and proliferating human fibroblasts and astrocytes following
inhibition of autophagic sequestration with 3-methyladenine (3MA).
Exposure of confluent fibroblast cultures to 3MA for two weeks
resulted in a significantly increased proportion of dying cells
compared to both untreated confluent cultures and dividing cells
with 3MA-inhibited autophagy. Similar results were obtained when
autophagic degradation was suppressed by the protease inhibitor
leupeptin. In 3MA- or leupeptin-exposed cultures, dying cells were
overloaded with undegraded autofluorescent material. The results
support a key role of biological lysosomal "garbage" accumulation in
the triggering of ageing and death of postmitotic cells, as well as
the anti-ageing role of cell division.

Int J Biochem Cell Biol. 2004 Dec;36(12):2365-75.
Aging as a catabolic malfunction.
Terman A, Brunk UT.
  Cellular degradative processes, which include lysosomal
(autophagic) and proteasomal degradation, as well as catabolism of
proteins by cytosolic and mitochondrial proteases, provide for a
continuous turnover of cellular components, such as damaged or
obsolete biomolecules and organelles. Inherent insufficiency of
these degradative processes results in progressive accumulation
within long-lived postmitotic cells of biological 'garbage' (waste
material), such as various oxidized proteins, functionally effete
mitochondria, and lipofuscin (age pigment), an intralysosomal,
polymeric, undegradable material. There is increasing evidence that
lipofuscin hampers lysosomal degradative capacity, thus promoting
the aggravation of accumulated damage at old age. Being rich in
redox-active iron, lipofuscin granules also may exacerbate oxidative
stress levels in senescent cells. Thus, increasing the efficiency of
cellular degradative pathways and preventing involvement of iron in
oxidant-induced lysosomal and cellular damage may be potential
strategies for anti-aging interventions.

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