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Andersen, 2004; Brookes
et al
., 2004). The
cumulative damage to DNA and proteins has
been observed in several pathologies includ-
ing cancer, atherosclerosis, diabetes and
Alzheimer's and Parkinson's diseases (Dhalla
et al.
, 2000; Andersen, 2004; Klaunig and
Kamendulis, 2004; Halliwell, 2006a,b). Such
accumulative and systemic ROS-induced
damage also underlies cell senescence and
ageing. Increasing evidence indicates, how-
ever, that homeostatic and physiological
levels of ROS are indispensable in regulat-
ing diverse cellular processes including ion
channel/transporter function (Zima and
Blatter, 2006), Ca
2+
spark production (Isaeva
et al.
, 2005; Yan
et al.
, 2008), protein kinase/
phosphatase activation, and gene expression
(Droge, 2002). The emerging view is that
ROS contribute to multiple essential intra-
cellular signalling processes ranging from
cell metabolism to ischaemic preconditioning
(Droge, 2002; Otani, 2004; Finkel, 2011).
Therefore, although the role of ROS as effec-
tors in many processes linked to ageing is
recognized, many reasonable doubts have
emerged questioning their regulatory func-
tions. Obviously, these doubts also compro-
mise the role of antioxidants in the ageing
process. Some authors therefore argue that
massive doses of antioxidants do not actu-
ally have a significant impact in extending
the lifespan of the human population. This is
in contrast to the well-known benefits of
antioxidant-rich foods consumption, which
could improve life quality. For instance, in
populations with antioxidant-rich diets a
lower relative risk to develop cardiovascular
diseases has been reported than for those
with a low intake of natural antioxidants
contained in fruit and vegetables (Joshipura
et al.
, 1999; Bazzano
et al.
, 2002; Hung
et al.
,
2004). It must be considered, however, that
antioxidants act in synergy with other vege-
tal macronutrients and micronutrients.
Interestingly, the search for antioxidant mol-
ecules is continuous, independent of the
debate related to their relevance. So, their
use in pharmaceutical, alimentary (func-
tional foods) and cosmetic industries is a
common practice.
Recently, a group of investigators from
the Stanford University found that the
expression of
elt-3, elt-5
and
elt-6
genes
changes during the normal ageing process
of
Caenorhabditis elegans
(Budovskaya
et al.
, 2008). These genes were previously
identified as responsible for the production
of the erythroid-like transcription factors:
EL-3, ELT-5 and ELT-6. The regulatory func-
tion of these factors is strongly associated
with the lifespan of
C. elegans
. Authors
found no evidence that age regulation of the
elt-3
transcriptional activity circuit is
caused by cellular damage or environmen-
tal stresses. Moreover, they observed that
elt-3
expression in adult worms is control-
led by increased expression of the repres-
sors
elt-5
and
elt-6
. In summary, the authors
propose that a change in the regulation of
these genes is caused by age-related drift of
an intrinsic developmental programme that
becomes imbalanced in old age. These
results must be considered with care, how-
ever, because worms only live 3 weeks and
humans could reach 70 or more years. In
line with these results, Bonawitz
et al.
(2007) found that the activity of the target of
rapamycin (TOR) negatively regulates
lifespan in yeast (Bonawitz
et al.
, 2007).
The TOR pathway is a major nutrient-
sensing pathway that, when genetically
downregulated, increases lifespan in evolu-
tionarily diverse organisms including mam-
mals. In the presence of glucose, the deletion
of the
TOR1
gene leads to an increase in
mitochondrial activity, promoting chrono-
logical lifespan (reviewed by Stanfel
et al.
,
2009). Interestingly, such respiratory activ-
ity does not lead to cellular ROS produc-
tion, because oxidation of the mitochondrial
electron transport chain is facilitated. So,
intramitochondrial oxygen levels are low,
limiting ROS production and accumulation.
Stanfel and coworkers (2009) propose
that pharmacological inhibition of the
TOR pathway should mimic the results
observed with
tor1
D cells. The central
component of this pathway, TOR kinase, is
the target of the inhibitory drug rapamy-
cin (Fig. 2.1), a highly specific and well-
described drug approved for human use. The
investigators found that feeding rapamy-
cin to adult
Drosophila
produces a lifespan
extension that mimics those observed in
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