LETTER TO THE EDITOR
A growing role for hypertrophy in senescence
YEAST RESEARCH
DOI: 10.1111/1567-1364.12015
Over 50 years ago, Mortimer and Johnson first appreciated that yeast could be used to study both the causes
and consequences of cellular aging (Mortimer & Johnston, 1959). In this model, the number of daughter buds
produced by a virgin mother cell is referred to as its
replicative life span (RLS), and the first hypothesis put
forward to explain yeast senescence proposed that cell size
may limit life span (Mortimer & Johnston, 1959). While
it is well accepted that yeast increase in size with age, the
possibility that size limits life span has been highly
debated. As yeast cell size scales with ploidy (diploid cells
are larger than haploid cells and so on), some of the earliest studies compared the RLS of haploid cells to diploid
or cells of increasing ploidy. Despite the correlation
between ploidy and cell size, a clear relationship between
ploidy and RLS has not been observed. For example,
while diploid cells live longer than smaller haploids, RLS
is shortest in hexaploid cells, which are presumably the
largest (Johnston, 1966; Muller, 1971; Kaeberlein et al.,
2005b). Furthermore, subsequent studies provided evidence both in favor of and against a role for cell size in
senescence (Muller, 1985; Egilmez & Jazwinski, 1989;
Egilmez et al., 1989, 1990; Kennedy et al., 1994). Muller
demonstrated that in zygotes, RLS is dominantly inherited from the partner with the shortest life span expectancy (Muller, 1985). In all cases, the older and
presumably larger of the fused haploids determined the
life span of the zygotes (Muller, 1985). Furthermore, large
virgin daughters display a significantly decreased RLS
(Johnston, 1966; Egilmez et al., 1989; Kennedy et al.,
1994). Yet, the demonstration that the use of alpha factor
to produce abnormally large cells did not reduce RLS has
led to the long-standing conclusion that cell size does not
have a causative role in aging (Kennedy et al., 1994; Sinclair et al., 1998a, b; Lin & Sinclair, 2008). Instead, the
current paradigm favors the hypothesis that cellular aging
is a direct result of the accumulation of ‘senescence factors’.
Initial studies suggested that a cytoplasmic factor produced predominantly by mother cells influenced RLS in
both mothers and daughters (Egilmez & Jazwinski, 1989;
Kennedy et al., 1994). Shortly afterward, a series of elegant experiments identified autonomously replicating
extrachromosomal ribosomal DNA circles (ERCs) as the
‘senescent factor’ (Sinclair & Guarente, 1997; Defossez
ª 2012 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
et al., 1998). First, it was demonstrated that ERCs were
predominantly present in old cells but absent in young
cells (Sinclair & Guarente, 1997; Defossez et al., 1998).
Moreover, ERCs accumulated as yeast cells aged, but
more importantly, the induction of ERCs in young cells
dramatically reduced RLS (Sinclair & Guarente, 1997;
Defossez et al., 1998). Thus, the case that ERCs caused
aging and modulated RLS in yeast appeared to be open and
shut (Sinclair & Guarente, 1997; Defossez et al., 1998).
However, incongruities with this hypothesis soon
appeared. First, it was reported that growth into stationary phase reduces RLS independent of ERC levels leading
the authors to suggest that factors other than ERCs can
determine life span (Ashrafi et al., 1999). Subsequently, it
was discovered that the RAD52 gene product is required
for ERC formation (Park et al., 1999). Although rad52
mutants lacked ERCs, they were surprisingly short-lived
(Park et al., 1999). While it is likely that rad52 mutants
are short-lived due to the accumulation of DNA damage,
a number of studies have demonstrated a lack of correlation between ERC levels and RLS (Ashrafi et al., 1999;
Park et al., 1999; Piper et al., 2002; Kaeberlein et al.,
2004; Kaeberlein & Powers, 2007; Ganley et al., 2009;
Lindstrom et al., 2011). For example, it has been
suggested that the fob1 longevity mutant extends RLS by
reducing ERC levels (Defossez et al., 1999). However,
recently it has been demonstrated that ERCs accumulate
to high levels in fob1 cells (Lindstrom et al., 2011).
Finally, the lack of a clear-cut understanding of the mechanism whereby ERCs regulate RLS has facilitated the
necessity for in-depth genetic analyses of the genetic pathways that modulate aging.
To answer this call, a number of elegant genetic studies
and screens in the past decade have identified > 60 genes,
which when deleted dramatically extend RLS (Kaeberlein
et al., 2005a, b; Lin & Sinclair, 2008; Steffen et al., 2008,
2012; Steinkraus et al., 2008; Kaeberlein, 2010). Many of
these genes function in highly conserved pathways
involved in nutrient sensing and ribosome biogenesis.
However, despite this tremendous progress, much still
remains to be learned about the mechanisms that modulate aging in yeast to determine the onset of senescence.
In addition, these studies have not yet clarified the mechanism whereby ERCs regulate aging. For example, almost
all of the longevity mutants tested thus far appear to
FEMS Yeast Res 13 (2013) 2–6
Letter to the Editor
extend RLS via mechanism independent of ERC levels
(Delaney et al., 2011). Furthermore, in the past few years,
the potential role of cell size in aging has again reared its
head, and reinvigorated the debate that hypertrophy may
be involved in the onset of senescence (Demidenko &
Blagosklonny, 2009a, b; Demidenko et al., 2009a, b; Yang
et al., 2011). Specifically, based on new evidence in yeast
and mammalian cells, the conclusion that cell size and/or
hypertrophy has no role in the determination of cellular
life span needs to be re-evaluated (Demidenko & Blagosklonny, 2008; Demidenko et al., 2009a, b; Yang et al.,
2011).
The key point in this debate centers around whether
increased cell size and/or hypertrophy actually reduces
RLS or is merely correlative with senescence in yeast. To
date, four experiments favor a causative role for increased
cell size and/or hypertrophy in senescence (Egilmez &
Jazwinski, 1989; Zadrag et al., 2006; Zadrag-Tecza et al.,
2008; Yang et al., 2011). First, although initial experiments with alpha factor demonstrated that RLS was not
reduced despite increased size (Kennedy et al., 1994),
follow-up experiments have concluded the opposite (Zadrag et al., 2006; Bilinski et al., 2012a, b). Second, akin to
the induction of ERCs, the induction of hypertrophy via
the rapid increase of cell size dramatically decreased RLS
in the ssf1D longevity mutant (Yang et al., 2011). As the
conditions used to induce hypertrophy are relatively
severe, these experiments do not rule out another mechanism (e.g. an increase in extra chromosomal rDNA circles
(ERCs), rDNA instability, or the rapid accumulation of
protein aggregates). However, it seems unlikely that this
occurred during the 3–5 h induction. Nonetheless, these
observations have fueled the recent debate regarding a
potential role for cell size and/or hypertrophy in yeast
senescence (Henderson & Gottschling, 2008; Bilinski
et al., 2012a, b; Ganley et al., 2012; Kaeberlein, 2012).
Critics of the hypothesis supporting a role for cell size
and/or hypertrophy in aging have raised three major
points of contention which are detailed below: (1) Hypertrophy may only be relevant in aged cells; (2) Evidence
that cell size reduction extends life span is lacking; and
(3) Not all long-lived cells are small and vice versa.
Under the current aging paradigm, RLS is proposed to
be completely regenerated in daughter cells (Sinclair
et al., 1998a, b; Henderson & Gottschling, 2008). Put
another way, daughters of middle age mothers are proposed to be born with full life span expectancy. One
exception to this is the observation that very old mothers
give rise to large daughters with a dramatically shortened
RLS (Johnston, 1966; Egilmez et al., 1989; Kennedy et al.,
1994). A corollary to this is that hypertrophy may only
be relevant in old cells. However, even moderate increases
in cell size reduce life span in virgin daughters (Kennedy
FEMS Yeast Res 13 (2013) 2–6
3
et al., 1994; Yang et al., 2011). In fact in wild-type cells,
granddaughter and great-granddaughters born to larger
than normal virgin wild-type mother cells are themselves
moderately larger than average and still display a moderately shortened life span (Kennedy et al., 1994; Yang
et al., 2011). It has been stated that ‘there is no clear connection between the majority of genes that when deleted
increase longevity (Delaney et al., 2011) and hypertrophy’
(Ganley et al., 2012). However, we have recently examined > 50 gene deletions or conditions that alter RLS and
found a remarkable correlation between the degree of
hypertrophy and life span (Yang et al., 2011, B.L. Schneider, unpublished).
A second important point centers on the relationship
between reduced cell size and life span extension. It has
been pointed out that ‘it is important to show that
genetic manipulations targeted to reduce cell size do
result in increased life span’ (Ganley et al., 2012). In this
respect, deletion of the WHI5 gene (the yeast ortholog of
the pRB tumor suppressor) significantly reduces the size
and extends the RLS of large cells (e.g. strains with a
deletion of the CLN3 gene, the yeast equivalent of cyclin
D) and other short-lived mutants (Yang et al., 2011; B.L.
Schneider, unpublished). Moreover, when ~ 850 cells were
assessed individually, a very strong correlation between
birth size and RLS was identified (Yang et al., 2011; B.L.
Schneider, unpublished). In addition, classic studies by
Muller demonstrated that growth on agar plates containing ethanol, which is well established to reduce cell size,
markedly increased RLS (Muller et al., 1980; Schneider
et al., 2004). Nonetheless, this issue needs to be further
developed.
A final question addresses the lack of a complete correlation between cell size mutants and life span. Specifically,
the point was raised that not all small (whi) mutants are
long-lived nor are all large cell mutants short-lived (Kaeberlein, 2012). It was further pointed out that only a
small number of mutants have been examined thus far
(Kaeberlein, 2012). However, to date, more than 25 whi
mutants have been tested and ~ 80% are long-lived (Yang
et al., 2011; B.L. Schneider, unpublished). Of particular
note, in at least two cases with duplicated genes (e.g.
RPL42a and RPL42b: genes that encode proteins in large
ribosomal subunit), the deletion of one homolog results
in small, long-lived cells whereas deletion of the other
homolog results in cells that are neither small nor longlived (Yang et al., 2011; B.L. Schneider, unpublished).
Moreover, of the ~ 20 large cell mutants examined thus
far, ~ 75% are short-lived (Yang et al., 2011, B.L. Schneider, unpublished). Thus, while not absolute, there is
clearly a correlation between size and RLS.
The hypothesis that hypertrophy is the cause of replicative aging in yeast has recently been championed and a
ª 2012 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
4
Letter to the Editor
13
11
Senescence
Lge
whi
30
40
0
5
5
20
Generations
WT
Senescence
7
7
7
5
10
(c)
Lge
whi
whi
0
WT
9
11
Microns
11
9
Lge
(b)
Microns
WT
Senescence
Microns
13
(a)
true in both wild-type cells and in mutants that alter cell
size (Fig. 1a). Even when they have the same GPG, large
virgin cells attain a senescent size much sooner than do
small virgin cells, and therefore, have a shorter RLS
(Fig. 1a). Third, mutations can alter the average rate of
GPG (Fig. 1b and c). Frequently, these mutations have a
concordant effect on cell size (Fig. 1b). For example, deletion of the WHI5 gene reduces cell size and decreases
GPG while deletion of the CLN3 gene increases both cell
size and GPG (Fig. 1b). The end result is a synergistic
effect on RLS; these types of whi mutants dramatically
lengthen RLS, while the converse is true for those types
of large cell mutants (Fig. 1b). This model may also help
explain how a large number of genes involved in ribosomal biogenesis modulate RLS (Steffen et al., 2008; Yang
et al., 2011). However, size mutants can also have discordant effects on GPG (Fig. 1c). For example, a given whi
mutant could increase GPG to such an extent that the
increased rate of hypertrophy negated the life span
extension effects of a small birth size (Fig. 1c). These
observations could explain why not all whi mutants are
long-lived nor are all large cell mutants short-lived. However, this working model does implicate both cell size and
hypertrophy as factors impacting RLS. While the molecular mechanisms responsible for these observations are not
known, the possibility that ERCs and hypertrophy
concomitantly regulate RLS is discussed below.
A number of recent publications have demonstrated
that the repression of cell growth in mammalian cells
reduces cell size and increases life span supporting a more
9
13
working model put forward by Bilinski et al. (2012a, b).
However, this model may need some minor revamping.
For instance, they suggest that cells from 0 to 20 generations with a size below the ‘minimal volume for allowing
entry into the cell cycle’ still cycle and age (Bilinski et al.,
2012a, b). This does not happen; cells below what is
referred to as ‘critical cell size’ do not cycle or bud until
that size is surpassed (B.L. Schneider et al., 2004). Moreover, this ‘critical cell size’ increases with age (Johnston,
1977). In addition, the Bili
nski et al. hypertrophy model
fails to take into account the rate at which cells increase
in size which has a profound effect on RLS (Yang et al.,
2011).
The hypertrophy model that we favor proposes that
both cell size and the rate of hypertrophy as measured by
the rate of growth per generation (GPG) are major determinants of cellular life span (Fig. 1). By measuring the
average size of virgin daughters at the beginning of an
aging assay (i.e. their diameter after they have been separated and removed from mother cells) and at the end of
their life span, the total increase in diameter over a cell’s
RLS can be calculated. Subsequently, by dividing the total
increase in diameter by the mean RLS, the average GPG
can be determined and is reflected by the slope of lines
shown (Fig. 1). In so doing, three general observations
have been made. First, yeast cells enter senescence at a
relatively constant cell size indicated by the gray rectangle
in Fig. 1 (Yang et al., 2011). Second, RLS is proportional
to birth size. In general, large cells are short-lived, and
small cells are long-lived (Fig. 1a). Importantly, this is
10
20
Generations
30
40
0
10
20
30
40
Generations
Fig. 1. Working model: birth size and hypertrophy as measured by GPG modulate the RLS of yeast. (a) Birth size modulates RLS. Wild-type (WT)
diploid cells born at an average diameter of ~ 7 µm grow to an average size of ~ 12 µm before entering senescence (indicated by shaded gray
bar). In contrast, in certain large cell (Lge) mutants, virgin daughters are born abnormally large (e.g. ~ 9 µm) but still grow (bold line) at the same
rate per generation as wild-type cells demonstrated by the common slope of the parallel lines. Nonetheless, because they were born abnormally
large, they reach senescent size sooner, and therefore, have a reduced RLS. The converse is true for whi mutants (dashed line). (b) Synergistic
size mutants concordantly modulate birth size and GPG. In this case, some large cell mutants (Lge) (e.g. cln3) increase both birth size and GPG
(bold line). Conversely, specific whi mutants (e.g. whi5) are born small and have a lower than normal GPG (dashed line). In both cases, the lines
signifying the rate of GPG are no longer parallel. The slope of Lge mutants with a high GPG increases, while the slope of the whi mutants with a
low GPG decreases. This accounts for a synergistic effect on RLS; high GPG further reduces RLS in short-lived Lge cells and vice versa. (c)
Discordant cell size mutants disconnect GPG from birth size. In this case, whi mutations could reduce birth size but increase GPG. The end result
would be small cells that grow and age fast (high GPG; bold line). Conversely, some large cell mutants could increase birth size but decrease
GPG resulting in large cells that grow and age slowly (low GPG; dashed line).
ª 2012 Federation of European Microbiological Societies
Published by Blackwell Publishing Ltd. All rights reserved
FEMS Yeast Res 13 (2013) 2–6
Letter to the Editor
generalizable role for hypertrophy in aging (Demidenko
& Blagosklonny, 2008, 2009a, b;, Demidenko et al.,
2009a, b). Moreover, there is a growing consensus (Blagosklonny & Hall, 2009; Yang et al., 2011; Blagosklonny,
2012, Bilinski et al., 2012a, b; Ganley et al., 2012; Kaeberlein, 2012) that the current aging paradigm should be
modified to include the possibility that hypertrophy may
function as an ‘aging factor’. Indeed, one hypothesis that
should be considered is that perhaps ERCs induce hypertrophy. The current paradigm posits that ERCs may
shorten life span by titrating away key transcription factors. We have found that the ERC DNA sequence
contains two consensus and nine near consensus (6/7
identical bases) binding sites for the Swi4/Swi6 (SBF) and
Mbp1/Swi6 (MBF) transcription factors. Importantly,
deletion of either of these transcription factors or over
expression of their binding sites induces hypertrophy and
increases cell size (Jorgensen et al., 2002; Wang et al.,
2009). Thus, the possibility remains that ERCs titrate SBF
and MBF away from their key promoters thereby inducing hypertrophy and shortening RLS. This potential
mechanism should be further evaluated. Nonetheless,
aging is clearly a very complex process, and it is highly
likely that multiple genetic pathways coordinately determine RLS. Finally, we concur with both Ganley et al. and
Kaeberlein that many elegant genetic studies in model
systems point to a high degree of conservation of the longevity modulating pathways and continued studies in
genetically tractable model organisms are essential for the
elucidation of the mechanisms involved in life span determination.
Acknowledgements
We would like to thank C. Schneider, C. Zahner, and
anonymous reviewers for critical insights. B.L.S. was supported by the NIH (Grant nos R01GM077874 and
R01GM077874-04S1) and the Ted Nash Long Life Foundation.
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Jill Wright, Huzefa Dungrawala
Department of Cell Biology and Biochemistry
Texas Tech University Health Sciences Center
Lubbock, TX, USA
Robert K. Bright
Department of Immunology and Molecular Microbiology
Texas Tech University Health Sciences Center
Lubbock, TX, USA
Brandt L. Schneider
Department of Cell Biology and Biochemistry
Texas Tech University Health Sciences Center
Lubbock, TX, USA
E-mail: [email protected]
FEMS Yeast Res 13 (2013) 2–6