Telomeres
The
2009 Nobel Prize in Physiology or Medicine was awarded to Elizabeth Blackburn,
Carol Greider and Jack Szostak for their contributions to our understanding of
how the ends of eukaryotic chromosomes, telomeres, are maintained by a
specialized reverse transcriptase, telomerase. This award is the closest Nobel
Prize to date related to aging. Of course, the major significance of the work
relates to basic cell biology and cancer, rather than aging research. In fact,
whereas telomere shortening explains the Hayflick limit (replicative
senescence) in human cells, it cannot explain the difference in longevity
between mice and men. But there may be other links between telomeres and
aging. In 2009, several publications by Epel, Blackburn and co-workers provide
a new link between telomere length and age-related diseases. As published in
the first issue of Aging, the rate of telomere shortening in peripheral
leukocytes predicts mortality from cardiovascular disease in elderly men [1]. Even more intriguingly, pessimism
correlates with short leukocyte telomeres and elevated interleukin (IL)-6 in
post-menopausal women [2]. The cause-and-effect relationship between telomere
length and these physiological endpoints is unknown, but several non-mutually
exclusive explanations can be proposed. Rapid telomere shortening may indicate
a cellular hyper-activation, hyper-proliferation and/or hyper-secretory
phenotypes often associated with cellular senescence, stem cell exhaustion and
diseases of aging.
In agreement with these possibilities, telomere length
was shown to regulate the expression of interferon-stimulated gene 15 (ISG15).
Short-telomeres up-regulated ISG15 independent of DNA damage signaling. This
finding demonstrated for the first time that an endogenous human gene can be
regulated by telomere length prior to the onset of telomere dysfunction and DNA
damage signals. It was suggested that the upregulation of ISG15 by telomere
shortening may contribute to the chronic inflammation associated with human
aging [3]. Pertinent to this idea, also in 2009, the secretion of inflammatory
cytokines such as IL-6 and IL-8 by senescent cells, whether made senescent by
dysfunctional telomeres or DNA damage, was shown to be suppressed by two
micro-RNAs (miR-146a and 146b) [4]. It was proposed that these micro-RNAs
modulate inflammatory responses by affecting signal transduction pathways that
contribute to a larger senescence associated secretory phenotype. It will be of
interest to know whether miR-146a/b also suppresses ISG15 expression, and if
this effect is influenced by telomere status.
It was also demonstrated that dysfunction
of a telomere-binding protein is sufficient to produce severe telomeric damage
in the absence of telomere shortening, resulting in premature tissue
degeneration and development of neoplastic lesions [5]. New insight has been
gained in the understanding of how telomeres are maintained and how the
processes of DNA repair occur in telomeres. For example, it appears that the
guardians of the genome, the RecQ helicases, actively participate in this
repair process [6].
Damaged telomeres were also found to be the major factor
contributing to the wide variability in the amount of DNA damage signaling in
human tumor cell lines, findings that may help clarify the relative
contributions of non-telomeric DNA double-strand breaks and damaged telomeres
to levels of genomic instability [7].
DNA
damage response and aging
In
2009, it was demonstrated that the persistent (but not transient) DNA damage
response (DDR) associated with senescent cells is essential for their ability
to express and secrete inflammatory cytokines [8]. Cell surface-bound IL-1alpha
is essential for the senescence-associated secretion of IL-6 and IL-8, 2
proinflam-matory cytokines, reinforcing the senescence phenotype [9].
Both
the initiation and maintenance of cytokine secretion required the DDR proteins
ATM, NBS1 and CHK2, but not p53. ATM was also essential for IL-6 secretion
during oncogene-induced senescence and by damaged cells that bypass
senescence. It was proposed that this activity of the DDR allows senescent
cells to communicate their compromised state to the surrounding tissue [8]. In
addition, a DDR may occur in senescent cells even in the absence of detectable
DNA damage [10]. This pseudo-DDR is a marker of cellular hyperactivation and
is inhibited by rapamycin [10], a clinically approved drug that decelerates
cellular senescence [11]. Thus, persistent DDR signaling, regardless of DNA
damage, may be a part of the senescent phenotype.
It
was shown that longevity extension mutations in the yeast SCH9, the yeast
homolog of the conserved pro-aging gene S6K (Ribosomal Protein S6 Kinase),
caused a major reduction in age-dependent DNA damage by lowering the activity
of error-prone DNA repair genes [12].
Also,
age-dependent deterioration of nuclear pore complexes causes an increase in
nuclear permeability and the leaking of cytoplasmic proteins into the nucleus
in postmitotic cells [13].
The
ability to respond to stress decreases with age. Stress-responding factors
which regulate transcription can influence longetivity. In 2009, Westerheide
et al demonstrated that stress-induced regulation of heat shock factor 1
(HSF-1) by the deacetylase SIRT1 (sirtuin 1) may play a role in the regulation
of life span [14]. Defining the targets of sirtuins may help to understand the
importance of transcriptional regulation in age-related diseases.
An
intriguing possibility is that the response of the cells to certain types of
DNA damage (e.g. DNA breaks) results in epigenetic changes that alter gene
expression [15]. These changes do occur in mammals and it will be interesting
to test whether these epigenetic changes in response to DNA damage are
associated with, or can actually cause aging.
Mitochondria,
oxidative stress and aging
On
the other hand, the free radical theory, which posits that aging is caused by
an accumulation of oxidative damage, was critically questioned in 2009.
First, overexpression of major antioxidant enzymes, which decrease free
radicals, did not extend the lifespan of mice [16]. Second, deletion of
mitochondrial superoxide dismutase (Sod-2) extended life span in Caenorhabditis
elegans [17]. Third, life span extension by dietary restriction was not
linked to protection against somatic DNA damage in Drosophila melanogaster
[18]. Fourth, Sod-2 haploinsufficiency did not accelerate murine aging, even
in mice with dysfunctional telomeres [19]. In addition it was demonstrated that
the reduced energy metabolism and the increased oxidative stress in the mitochondria
of young Mclk1+/- mice results in an almost complete protection from the
age-dependent loss of mitochondrial function. Moreover, this altered
mitochondrial condition is linked to a significant attenuation of the rate of
development of oxidative biomarkers of aging. Thus, this study indicates that
mitochondrial oxidative stress is not causal to aging [20]. It was reported
that RNAi of five genes encoding components of mitochondrial respiratory
complexes I, III, IV, and V leads to increased life span in flies. Long-lived
flies with reduced expression of electron transport chain (ETC) genes do not
consistently show reduced assembly of respiratory complexes or reduced ATP
levels. In addition, extended longevity is not consistently correlated with increased
resistance to the free-radical generator paraquat [21].
These results are in agreement with
previous papers showing that antioxidants overexpression causes minor effects
in life span extension in yeast, flies, and mice compared to those caused by
mutations in signal transduction genes. It is likely that increase protection
against superoxide must be accompanied by a number of other changes to be
effective in life span extension. For instance, LON, a AAA protease located in
the mitochondrial matrix, increases stress tolerance, mitochondrial oxygen
consumption, while decreasing oxidative damage of proteins in the fungal aging
model Podospora anserine [22]. In the same model organism, deletion of a
gene encoding a O-methyltransferase, which decrease levels of reactive oxygen
species, leads to a decreased lifespan [23].
Calorie
restriction (CR)
Caloric
restriction (CR) without malnutrition delays aging and extends life span in
diverse species; however, its effect in primates had not been clearly
established. In 2009, a 20-year longitudinal study of adult-onset CR in rhesus
monkeys demonstrated that moderate CR lowered the incidence of aging-related
deaths. At the time point reported, 50% of control animals had survived,
compared with 80% of CR animals. CR delayed the onset of several
age-associated pathologies such as diabetes, cancer, cardiovascular disease and
brain atrophy [24]. The CR trial in primates raised hope that CR might be
effective in humans.
In
2009, numerous studies continued to establish links between caloric restriction
(CR) and longevity signaling pathways, including Sir2 (sirtuin) and p53 in D.
melanogaster [25] and the E3 ubiquitin ligase WWP-1 in C. elegans
[26] as well as upstream and downstream components of the TOR (Target of
Rapamycin) pathway: RHEB-1 in C. elegans [27], Tor1 and Sch9 (a homolog
of the mammalian kinases Akt and S6K) in yeast [28], and 4E-BP (Eukaryotic
Translation Initiation Factor 4E Binding Protein) in Drosophila [29]. It
was shown that glucose shortens the life span of C. elegans by downregulating
DAF-16/FOXO activity and aquaporin gene expression [30]. In addition, the HIF
(hypoxia inducible factor) pathway was implicated in aging and longevity in C.
elegans [31,32]. The different results of two studies have been in general
reconciled [33]. In 2009, it has also been shown that in C. elegans CR is mediated
by a network of independent, but overlapping pathways [34], suggesting a ‘CR
network'. Notably, neuronal SIRT1 regulated endocrine and behavioral responses
to CR [35].
It
has been shown that disruption of growth hormone receptor (GHR) prevents calorie
restriction from improving insulin action and longevity [36]. In normal mice,
CR increased insulin sensitivity in liver and muscle. In GHRKO mice, intrinsic
insulin-sensitivity could be attributed to a reduction of inhibitory serine
phosphorylation of IRS-1 (Insulin receptor substrate 1) in muscle. CR failed to
further increase insulin signaling (insulin sensitivity) in GHRKO mice as
compared to normal mice, likely explaining the absence of CR effects on
longevity in these long-lived mice [36].
Finally,
it was tested whether reallocation of nutrients from reproduction to somatic
maintenance could explain the life extending effect of CR. If this were the
case, long life under dietary restriction and high fecundity (reproduction)
under full feeding would be mutually exclusive. Adding methionine alone to the
dietary restriction condition was necessary and sufficient to increase
fecundity as much as did full feeding, but without reducing lifespan.
Reallocation of nutrients therefore does not explain the responses to dietary
restriction. In contrast, reduced activity of the insulin/insulin-like growth
factor signaling protected against the shortening of lifespan with full feeding
[37].
Pharmacologic
intervention
The
ultimate goal of biomedical research is the development of therapeutic drugs.
As shown previously, activation of mTOR (mammalian Target of Rapamycin) is
required for acquiring senescent phenotype in p21-arrested human cells, whereas
deactivation of mTOR converts senescence into quiescence. In 2009, it was
further demonstrated that the inhibitor of mTOR rapamycin decelerated cellular
senescence of p21-arrested human and mouse cells [11]. Similarly, inhibitors of
PI-3K and MEK, LY-294002 and U0126, deactivated mTOR and suppressed cellular
senescence (converting it into quiescence) [38], defining direct and indirect
mTOR inhibitors as aging-suppressants or gero-suppressants.
The
most striking event of the year was the demonstration that rapamycin,
administrated to middle-aged (600 day old) mice, significantly extended their
life span [39]. The effect was seen at three independent test sites in
genetically heterogeneous mice, chosen to avoid genotype-specific effects on
disease susceptibility [39]. Rapamycin also prolonged the life of 22-month old
mice [40]. [Note: publications by Bjedov et al (Cell Metab 2010 Jan) and by
Moskalev and Shaposhnikov (coming in print 2010) that rapamycin extends life
span in Drosophila will be reviewed next year].
It was shown that clioquinol, a metal
chelator that has beneficial effects in several models of neuro-degenerative
diseases, inhibits the activity of the mitochondrial enzyme CLK-1 in mammalian
cells. Clioquinol-treated nematodes and mice presented a variety of phenotypes
produced by mutational reduction of CLK-1. Given that reduction of CLK-1 slows
down aging in these organisms, these results suggest that clioquinol (by
inhibiting CLK-1) may slow down the aging process [41].
Finally,
as a follow-up of the work on the anti-aging effects of mitochondria-targeted
antioxidant SkQ1 [42], it was demonstrated that Sk inhibits age-dependent
involution of the thymus in normal and senescence-prone rats [43].
Stem
cells and aging
In
2009, several lines of evidence suggested that overactivation of signaling
pathways might cause exhaustion of stem cells and that vice versa ‘longevity
genes' could prevent stem cell exhaustion. Thus, mTOR mediated Wnt-induced epidermal
stem cell exhaustion and aging phenotypes in skin [44]. Further,
hyper-activation of mTORC1 caused hyper-proliferation and subsequent exhaustion
of hematopoietic stem cells. Pharmacological approaches showed that PTEN, TSC1
and PML regulate hematopoietic stem cell (HSC) maintenance through mTORC1
[45]. In addition, FOXO transcription factors were found to be necessary for
adult neural stem cell homeostasis [46,47]. Importantly, stem cell aging
could be suppressed pharmacologically [40,44]. The PI3K-AKT-FoxO pathway is
integral to lifespan regulation in lower organisms plays a prominent role in
neural stem/progenitor cell (NSC) proliferation and renewal. FoxO-deficient
mice show initial increased brain size and proliferation of neural progenitor
cells during early postnatal life, followed by precocious significant decline
in the NSC pool and accompanying neurogenesis in adult brains [46].
In
addition, functions of aging organs can be rejuvenated by young supporting stem
cells. As published in the first issue of Aging, once-monthly infusions
of bone marrow (BM)-derived cells from young adult female mice sustained the
fertility of aging females long past their time of normal reproductive failure
[48]. The fertility-promoting effects were observed regardless of whether the
infusions were initiated in young adult or middle-aged females, and were
specific for bone marrow harvested from female donors. This "rejuvenation" did
not depend on the development of mature eggs from germline cells in the donor
marrow, but from host germline cells sustained by the infusions [48,49]. In
fact, very recent studies showed that aged mouse ovaries lacking oocytes retain
a rare population of germline stem cells that, when transplanted into a young
host ovarian environment, are able to generate immature oocytes contained
within follicles [49]. Thus, reproductive failure with age may be due, at least
in part, to deterioration of somatic microenvironments (niches) that support
stem cell function.
Nuclear
reprogramming and senescence
Much
interest has also been devoted in the past year to nuclear reprogramming of
differentiated cells into induced pluripotent stem (iPS) cells by using defined
factors. Understanding which factors facilitate the reprogramming process is
thought to give clues to the process of carcinogenesis. Inversely, nuclear reprogramming
could be also envisioned as a "rejuvenation process". In this regard, p53 and
p16INK4a tumor suppressor proteins were shown to be important in
limiting reprogramming [50-55]. Activation of p53 was suggested to be more
important in murine cells, whereas activation of p16INK4a appeared
the predominant barrier in human cells [50].
Of
particular importance to the field of regenerative medicine, which will need
patient-specific stem cells derived from older patients, is reprogramming
efficiency in fibroblasts from aged humans versus young humans. There is an
age-associated decline in reprogramming efficiency, which is largely reversed
by inactivation of the p16INK4a tumors suppressor gene, whose
expression is increased markedly with aging in several human and murine tissues
[50,55]. Along these lines, it was shown that the increased expression of
p16INK4a with aging could be measured on human peripheral blood samples, and
that an individual's p16INK4a expression was a good biomarker of their
"molecular age" [56]. The same group also provided further understanding of the
observed linkage of SNPs near the CDKN2a/b locus (which encodes the p16INK4a,
p15INK4b and ARF tumor suppressors) with human atherosclerotic
disease [57]. Expression of CDKN2a/b transcripts is decreased in
individuals harboring the risk alleles, suggesting that atherosclerotic disease
may result from aberrant, unrestrained proliferation. In this regard, studies
on mice overexposing the CDKN2a/b locus were found to have delayed aging and
extended longevity [58].
Genetics
of aging
In 2009, numerous publications extended
our knowledge on the role of sirtuins [35], TOR signaling [59,60], and the
stress response factors HSF-1 and DAF-16 [61] in aging. Of particular
importance, it was shown that deletion of the gene encoding Ribosomal Protein
S6 Kinase 1 (S6K1) and disruption of PKA extend the life span of mice [62,63],
whereas the gene encoding Eukaryotic Translation Initiation Factor 4E Binding
Protein (4E-BP) was shown to be essential for life span extension by CR in Drosophila
[29]. Moreover, 4E-BP was shown to act downstream of TOR to modulate cardiac
aging in Drosophila [64]. Finally, SIRT6 was shown to play a critical
role in DNA double-strand break repair [65].
In
2009, Kenyon and co-workers further uncovered mechanisms of their previous
observations made in 1999 (Hsin and Kenyon, Nature, 1999, 399:362-6) that in C
elegans and Drosophila the aging of the soma is influenced by the
germline: namely, when germline-stem cells are removed, aging slows and
lifespan is increased. In 2009, it was published that a predicted transcription
elongation factor, TCER-1, plays a key role in this process [66]. When the germ
cells are removed, the levels of TCER-1 rise in somatic tissues. This increase
is sufficient to trigger key downstream events, as overexpression of tcer-1
extends the lifespan of normal animals that have an intact reproductive system.
Intriguingly, TCER-1 specifically links the activity of a broadly deployed
transcription factor, DAF-16/FOXO, to longevity signals from reproductive
tissues [66]. In mice, Foxo1 integrates insulin signaling with mitochondrial
function, and inhibition of Foxo1 can improve hepatic metabolism during insulin
resistance and the metabolic syndrome [67].
A
prior work by Willcox et al (PNAS 2008, 105: 13987) showed that genetic
variation within the FOXO3A gene was strongly associated with human longevity.
Long-lived men also presented several additional phenotypes linked to healthy
aging, including lower prevalence of cancer and cardiovascular disease, and
high physical and cognitive function. Long-lived men also exhibited greater
insulin sensitivity associated with homozygosity for the FOXO3A GG genotype. In
2009, confirming the Willcox observation, the flurry of papers showed the
association between SNPs in the FoxO3A gene and extreme longevity in Japanese,
German, American, Italian, and Chinese populations [68-71].
There
were intriguing publications on the complex role of p53 in longevity. In Drosophila
melanogaster, p53 exerted developmental stage-specific and sex-specific
effects on adult life span, indicative of sexual antagonistic pleiotropy [72,73]. Further, an association between single nucleotide polymorphisms (SNPs) in
p53 pathway genes and human fertility suggested that p53 regulates the
efficiency of human reproduction. These results provide a plausible
explanation for selective pressure to retain some alleles in the p53 pathway,
and suggest that such alleles are a good example of antagonistic pleiotropy
[74].
Interestingly,
SNPs in the p21 gene correlated with longevity in an Italian population [75].
Several papers have highlighted an important role of p53 in tissue fitness
through its impact in preventing mobilization of stem cells harboring
persistent DNA damage (ie, dysfunctional telomeres) [76,77]. However, the
phenotypic outcome was tissue and context specific. In mouse epidermis deletion
of p53 rescued organ maintenance and body fitness of neborn mice with
dysfunctional telomeres [76]. In contrast, p53 deletion in the intestinal
epithelium accelerated tissue dystruction and shortened the lifespan of aging
telomere dysfunctional mice [77]. The latter phenotype was associated with
aberrant survival chromosomal instable stem cell clones leading to abnormal
differentiation and p53-independent apoptosis. The limitation of the survival
of chromosomal instable stem cells is likely to represent a key step in the
known role of p53 as a tumor suppressor. Also it was shown that the p53 family
member, TAp63, is essential for maintenance of epidermal and dermal precursors
and that, in its absence, these precursors senesce and skin ages prematurely
[78].
Model
systems continue to be instrumental in understanding the genetics of
longevity. The WRN gene defective in the premature aging disorder
Werner syndrome encodes a protein with both helicase and exonuclease activities
[79]. To dissect its genetic functions, human WRN was tested for its ability
to rescue sgs1-related phenotypes. WRN was shown to genetically
interact with topoisomerase 3 and restore the slow growth phenotype of sgs1
top3. WRN helicase but not exonuclease activity was genetically required
for restoration of top3 growth phenotype, demonstrating separation of
function of WRN catalytic activities. In a top3 mutant background, DNA
unwinding by WRN helicase may be deleterious to cell growth and genome
homeostasis [80].
In 2009, a few studies delved into the
genetics of the insulin-producing pancreatic beta-cell aging in humans and mice
[81-83]. A loss of beta-cell replication with aging is a contributor to
age-related increase in the incidence of type II diabetes. Prior work had
shown that p16INK4a tumor suppressor causes an age-dependent decline
in beta-cell replication. In 2009, it was reported that loss of Polycomb (PcG)
repression of p16INK4a mediated by the EZH2 histone methytransferase occurred
with aging in humans and mice [82]. In mice, somatic deletion of EZH2 led to
loss of beta-cell replication and diabetes, and these effects could be rescued
by concomitant deletion of p16INK4a and Arf.
This
work linked alterations of chromatin architecture with aging to expression of
anti-proliferative molecules. Bhushan and colleagues also reported a similar
regulation of p16INK4a expression with aging by the Bmi-1 PcG
protein, which functions in concert with EZH2 to repress p16INK4a
expression [81]. Lastly, it was shown that p38MAPK activates p16INK4a
with aging in beta-cells, suggesting a possible pharmacologic approach to
regulating aging of this tissue [83].
Autophagy
In
2009, the simple dogma that autophagy is always associated with or causes
senescence was challenged. Although autophagy remains a crucial anti-aging
mechanism, the relationship is likely to be complex. Thus, autophagy was shown
to be activated during cellular senescence, and activation correlated with
negative feedback in the PI3K-mTOR pathway. A subset of autophagy-related genes
was up-regulated during senescence: overexpression of one gene, ULK3, induced autophagy
and senescence. Furthermore, inhibition of autophagy delayed the senescence
phenotype, including senescence-associated secretion. These data suggest that
autophagy, and its consequent protein turnover, may mediate acquisition of the
senescence phenotype [84]. Inhibition of autophagy in adult Drosophila
[85] or C. elegans [86] was found not to affect longevity, however
autophagy was required for the increased life span caused by several
pharmocologic and genetic manipulations in yeast, Drosophila and C. elegans
[87-90], suggesting that autophagy may be limiting for life span under some
conditions but not others. Interestingly, resveratrol-mediated inhibition of
mammalian S6 kinase by resveratrol suppressed autophagy [91]. In 2009, several
reports further demonstrated that the TOR signaling pathway targets the
Atg1/Atg13 protein kinase complex to control autophagy [92-94]. Furthermore,
TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative
disease [95].
The
natural polyanion spermidine can extend the chronological and replicative life
span in yeast and increase the median and maximal longevity of fruit flies and
nematodes (C. elegans). Spermidine was found to act as a potent inducer
of autophagy in all species tested, including yeast, Drosophila, C. elegans
[96]. The antiaging effect of spermidine was abolished by the deletion or
depletion of essential autophagy genes in yeast, Drosophila and C.
elegans [96]. In mice, a dietary supplementation with polyanions (including
spermidine) also increases healthspan and lifespan [97], although the
dependency of this phenomenon on autophagy has not been addressed yet.
Spermidine likewise induces autophagy and longevity through its capacity to
inhibit histone acetylases in yeast cells [96].
Sirtuin-1
and that of its C. elegans orthologue induce autophagy in human and
nematode cells. Sirtuin-1 is also required for the induction of autophagy by
its allosteric activator resveratrol (both in human cells and nematodes),
culture in nutrient-free media (in human cells) and caloric restriction (in
nematodes). In C. elegans, it was found that activation of Sirtuin-1
extended longevity in an autophagy-dependent fashion. Thus, the knockdown of
the essential autophagy gene Beclin1/ATG6 abolished life span extension by
Sirtuin-1 activation [87]. These results underscore the contribution autophagy
to the regulation of longevity by pharmacological agents [98].
Post-transcriptional
gene regulation and aging
In
fact, 2009 saw an escalation in interest in microRNAs and other non-coding RNAs
implicated in aging and replicative senescence. A prominent example of this
regulation came studies of the mitogen-activated protein kinase (MAPK)
signaling component MKK4 (MAPK kinase kinase 4). MKK4 levels were elevated in
aging tissues and in senescent cells thanks to reductions in the abundance of
four microRNAs (miR-15b, miR-24, miR-25, and miR-141) that interacted with the
5'- and 3'-untranslated regions of the MKK4 mRNA and repressed its translation
[99].
The
other major class of post-transcriptional regulatory factors, RNA-binding
proteins (RBPs), were also the focus of important age-related studies in 2009.
Several RBPs that affect the turnover and translation of proteins implicated in
proliferation, survival, inflammation, neurodegeneration, and cancer (HuR,
AUF1, TIA-1, TTP) displayed elevated abundance in a broad array of human
tissues and in all ages, suggesting that their influence extends throughout the
human life span [100]. The RBP TTP (tristetraprolin) attracted especial
attention because it triggered replicative senescence [101]; in keeping with
the tumor-suppressive influence of replicative senescence, TTP was found to be
eliminated in certain cancers [102].
Circadian
clock
There is growing evidence for a link
between circadian rhythm, signal-transduction genes, metabolism, cancer and
aging [103,104]. The circadian clock gene period extended the health
span of aging in Drosophila melanogaster [105]. Further, circadian
control of the NAD+ salvage pathway by CLOCK-SIRT1 was demonstrated [106].
Intriguingly, light was found to activate MAPK (mitogen activated pathway
kinase) in zebrafish cells, and this light-dependent activation controlled DNA
repair [107]. In rats, circadian disruption induced by light-at-night
accelerates aging and promotes tumorigenesis in rats [108]. In mice, it was
reported that N-acetyl-L-cysteine (NAC), an antioxidant, ameliorated symptoms
of premature aging associated with the deficiency of the circadian protein
BMAL1 [109].
Cancer
and aging
CR
is known to slow aging and delay cancer. In 2009, it was reported that fasting
abrogates side effects caused by chemotherapy in cancer patients. Importantly,
for those patients in whom cancer progression could be assessed, fasting did
not prevent chemotherapy-induced reduction of tumor volume or tumor markers
[110]. The link between aging and cancer via p53 was shown to be complex in
2009. Thus, the ability of p53 to act as a defense against tumor progression
was shown to be age-dependent [111]. Further, Levine and co-workers previously
showed that p53 activity declines with age, and a recent study showed that p53
transcriptional activity is reduced in senescent cells [112]. Interestingly,
SIRT1 knockout mice, which do not live longer when calorically restricted, were
found to have normal rates of skin cancer but the ability of resveratrol, a
SIRT1 activator, to protect the mice was greatly reduced [113], indicating that
the anti-tumor activity of resveratrol is mediated at least in part by SIRT1.
Reduced
incidence and delayed occurrence of fatal neoplastic diseases in growth hormone
receptor/binding protein knockout mice. These changes of fatal neoplasms are
similar to the effects observed with calorie restriction and therefore could
possibly be a major contributing factor to the extended life span observed in
the GHR/BP KO mice. [114] Overall,
2009 was an exciting year for increasing our understanding of aging and its
relationship to age-related disease, and developing promising strategies and
candidates for pharmacological interventions into the aging process. Several
approaches in combination with drugs and diet may slow aging, although not
making it negligible [115].
Acknowledgments and announcements
We
apologize to the authors whose important publications were not discussed due to
space limitations or were simply overlooked. Here we referenced only papers published
in the 2009 calendar year. That was not an easy task given that most of
publications are the continuation of or based on previous research. We expect
to make this a tradition to publish ‘the year overview' every year. The next
year, the task will be easier, given that "Aging in 2010" will be the
continuation of "Aging in 2009".
Please
e-mail your reprints to us in December 2010 (editors@impactaging.com) or, even
better, please submit your best manuscripts for publication in Aging at papers@impactaging.com.
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