Forever young, slim and fit
Rapamycin to the rescue
It is an indisputable fact that sustained dietary restriction increases lifespan of organisms, from
yeast to mammals. Disputable, however, are mechanisms involved in this phenomenon. The
dietary restriction-driven reduction of oxidative metabolism that leads to a decrease in production
of reactive oxidants with DNA-damaging properties is one of the proposed mechanisms.1
Whereas accumulation of oxidant-induced DNA damage progressing with age have been repeatedly
demonstrated it is still debatable whether this is the only, or even the major cause of aging or
lifespan limitation. The inconsistencies plaguing the reactive oxidant (ROS) theory of aging were
persuasively presented in a recent review.2 The dietary restriction-driven reduction of metabolic
rate involves downregulation of the nutrientsensor mammalian target of rapamycin (mTOR),
the evolutionarily conserved serine/threonine protein kinase that is strongly implicated in stimulating
cell growth.3 TOR regulates two processes that can be accountable for the observed effect
of dietary restriction on longevity. One of them is the rate of protein synthesis which is modulated
by the effect of TOR on the ribosomal protein S6 kinase (S6K) and on the translation initiation
factor 4E-binding protein (4E-BP).4 Inhibition of protein synthesis e.g., through 4E-BP was
shown e.g. to promote longevity of Drosophila.5 It is therefore possible that inhibition of TOR
just leads to reduction in the rate of protein synthesis and this is the mechanism of its effect
prolonging longevity.6 Inhibition of translation may shift cell metabolism to physiological state
that favors maintenance and repair and this may lead to extension of lifespan.4 However,
regulation of autophagy is another process by which TOR may affect cell longevity. Autophagy
can be induced by stress and also by dietary restriction. Inhibition of TOR elicits autophagy
and prolongs life-span of C. elegans. However, because the latter effect requires the presence of
DAF-16/DOXO transcription factor the induction of autophagy alone is inadequate to prolong
these worms life.3 The involvement of forkhead box class DAF-16 transcription factor in regulation
of longevity was underscored in studies on Drosophila(dFOXO)7,8 and C. elegans (FoxA)9
in which an extension of lifespan was seen as a result of upregulation of this factor. It has been
suggested that the FOXO and TOR pathways are antagonistic to each other and nutrients promote
TOR and repress FOXO signaling, shortening lifespan.9 It should be noted that the ROS- and
TOR-associated mechanisms of aging are not mutually exclusive and interestingly, there are
several points of their convergence.2 In this issue of Cell Cycle, Demidenko et al.,10
present interesting observations that the mTOR inhibitor rapamycin attenuated the appearance
of senescence of cells of several human and rodent cell lines, induced by their arrest in the
cell cycle. In elegant experiments these authors demonstrate than ectopic expression of p21,
p16 or treatment with n-butyrate (which elevates p21) causes senescence of these cells, with the
classical features that include irreversible loss of cells ability to proliferation. Of importance,
rapamycin was effective both, in delaying the appearance of senescence phenotype detected
by various markers, and in preventing reproductive death, otherwise occurring as a result
of prolonged arrest in the cell cycle. The data are convincing and the authors conclude on an
optimistic note that “senescence can be pharmacologically suppressed.”
The in vitro induction of cell senescence by arrest in the cell cycle resembles the phenomenon
observed over four decades ago and then defined as growth imbalance.11 When
progression through the cell cycle (replication) is halted and cell growth in terms of translation,
transcription and protein accumulation continues the imbalance occurs and is reflected by cell
enlargement, increased ratio of protein or RNA to DNA and expression of other markers currently
considered characteristic of cell senescence. The function of the nutrient-sensor mTOR during
the arrest is to stimulate cell growth thereby promoting the imbalance. Expectedly, growth
inhibition by rapamycin whether by suppression of translation, enhancement of protein degradation
by autophagy, or by both mechanisms, slows down the development of the imbalance
(senescence) phenotype. Consistent with this mechanism is the earlier observation that growth
stimulation during cell cycle arrest enhances senescence.12 At organismal level the mTOR
may be compared to the taste-sensor which by enhancing taste stimulates our appetite and may
lead to obesity with all deleterious consequences such as type 2 diabetes. Rapamycin, in this
analogy, curtails the desire to eat (feel hunger) keeping us slim and healthy. It certainly does it
to individual cells. Can we have the “magic pill” with the ability to keep us “forever young”? This is obviously
too much to ask at present, but targeting mTOR appears to be the direction to follow to develop life prolonging and/or “rejuvenating” modalities.
References
1. Lombard DB, et al. Cell 2005; 120:497-512
2. Blagosklonny MV. Cell Cycle 2008; 7:3344-54.
3. Hansen M, et al. PLoS Genetics 2008: 4:e24
4. Hansen M, et al, Aging cell 2007; 6:95-110
5. Tettweiler G, et al, Genes Dev. 2005; 19:1840-3
6. Pan KZ, et al., Aging Cell 2007; 6:111-9
7. Hwangbo DS, et al., Nature 2004; 429:562-6
8. Giannakou ME, et al., Aging Cell 2007; 6:429-48
9. Sheaffer KL, et al., Curr Biol 2008; 18:1355-64
10. Demidenko ZN, et al., Cell Cycle 2009:
11. Cohen LS, Studzinski GP. J Cell Physiol 1967; 69:331-9.
12. Demidenko ZN, Blagosklonny MV. Cell Cycle 2008; 7:
3355-61.
Rapamycin to the rescue
It is an indisputable fact that sustained dietary restriction increases lifespan of organisms, from
yeast to mammals. Disputable, however, are mechanisms involved in this phenomenon. The
dietary restriction-driven reduction of oxidative metabolism that leads to a decrease in production
of reactive oxidants with DNA-damaging properties is one of the proposed mechanisms.1
Whereas accumulation of oxidant-induced DNA damage progressing with age have been repeatedly
demonstrated it is still debatable whether this is the only, or even the major cause of aging or
lifespan limitation. The inconsistencies plaguing the reactive oxidant (ROS) theory of aging were
persuasively presented in a recent review.2 The dietary restriction-driven reduction of metabolic
rate involves downregulation of the nutrientsensor mammalian target of rapamycin (mTOR),
the evolutionarily conserved serine/threonine protein kinase that is strongly implicated in stimulating
cell growth.3 TOR regulates two processes that can be accountable for the observed effect
of dietary restriction on longevity. One of them is the rate of protein synthesis which is modulated
by the effect of TOR on the ribosomal protein S6 kinase (S6K) and on the translation initiation
factor 4E-binding protein (4E-BP).4 Inhibition of protein synthesis e.g., through 4E-BP was
shown e.g. to promote longevity of Drosophila.5 It is therefore possible that inhibition of TOR
just leads to reduction in the rate of protein synthesis and this is the mechanism of its effect
prolonging longevity.6 Inhibition of translation may shift cell metabolism to physiological state
that favors maintenance and repair and this may lead to extension of lifespan.4 However,
regulation of autophagy is another process by which TOR may affect cell longevity. Autophagy
can be induced by stress and also by dietary restriction. Inhibition of TOR elicits autophagy
and prolongs life-span of C. elegans. However, because the latter effect requires the presence of
DAF-16/DOXO transcription factor the induction of autophagy alone is inadequate to prolong
these worms life.3 The involvement of forkhead box class DAF-16 transcription factor in regulation
of longevity was underscored in studies on Drosophila(dFOXO)7,8 and C. elegans (FoxA)9
in which an extension of lifespan was seen as a result of upregulation of this factor. It has been
suggested that the FOXO and TOR pathways are antagonistic to each other and nutrients promote
TOR and repress FOXO signaling, shortening lifespan.9 It should be noted that the ROS- and
TOR-associated mechanisms of aging are not mutually exclusive and interestingly, there are
several points of their convergence.2 In this issue of Cell Cycle, Demidenko et al.,10
present interesting observations that the mTOR inhibitor rapamycin attenuated the appearance
of senescence of cells of several human and rodent cell lines, induced by their arrest in the
cell cycle. In elegant experiments these authors demonstrate than ectopic expression of p21,
p16 or treatment with n-butyrate (which elevates p21) causes senescence of these cells, with the
classical features that include irreversible loss of cells ability to proliferation. Of importance,
rapamycin was effective both, in delaying the appearance of senescence phenotype detected
by various markers, and in preventing reproductive death, otherwise occurring as a result
of prolonged arrest in the cell cycle. The data are convincing and the authors conclude on an
optimistic note that “senescence can be pharmacologically suppressed.”
The in vitro induction of cell senescence by arrest in the cell cycle resembles the phenomenon
observed over four decades ago and then defined as growth imbalance.11 When
progression through the cell cycle (replication) is halted and cell growth in terms of translation,
transcription and protein accumulation continues the imbalance occurs and is reflected by cell
enlargement, increased ratio of protein or RNA to DNA and expression of other markers currently
considered characteristic of cell senescence. The function of the nutrient-sensor mTOR during
the arrest is to stimulate cell growth thereby promoting the imbalance. Expectedly, growth
inhibition by rapamycin whether by suppression of translation, enhancement of protein degradation
by autophagy, or by both mechanisms, slows down the development of the imbalance
(senescence) phenotype. Consistent with this mechanism is the earlier observation that growth
stimulation during cell cycle arrest enhances senescence.12 At organismal level the mTOR
may be compared to the taste-sensor which by enhancing taste stimulates our appetite and may
lead to obesity with all deleterious consequences such as type 2 diabetes. Rapamycin, in this
analogy, curtails the desire to eat (feel hunger) keeping us slim and healthy. It certainly does it
to individual cells. Can we have the “magic pill” with the ability to keep us “forever young”? This is obviously
too much to ask at present, but targeting mTOR appears to be the direction to follow to develop life prolonging and/or “rejuvenating” modalities.
References
1. Lombard DB, et al. Cell 2005; 120:497-512
2. Blagosklonny MV. Cell Cycle 2008; 7:3344-54.
3. Hansen M, et al. PLoS Genetics 2008: 4:e24
4. Hansen M, et al, Aging cell 2007; 6:95-110
5. Tettweiler G, et al, Genes Dev. 2005; 19:1840-3
6. Pan KZ, et al., Aging Cell 2007; 6:111-9
7. Hwangbo DS, et al., Nature 2004; 429:562-6
8. Giannakou ME, et al., Aging Cell 2007; 6:429-48
9. Sheaffer KL, et al., Curr Biol 2008; 18:1355-64
10. Demidenko ZN, et al., Cell Cycle 2009:
11. Cohen LS, Studzinski GP. J Cell Physiol 1967; 69:331-9.
12. Demidenko ZN, Blagosklonny MV. Cell Cycle 2008; 7:
3355-61.
] (almeno ci si consola...)
