A growing role for hypertrophy in senescence.
A growing role for hypertrophy in senescence.
复制标题
肥大在衰老中的作用越来越重要。
DOI：
10.1111/1567-1364.12015
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发表时间：
2013
影响因子：
3.2
通讯作者：
Schneider,BrandtL
中科院分区：
文献类型：
--
作者：
Wright,Jill;Dungrawala,Huzefa;Bright,RobertK;Schneider,BrandtL
通过独立于ERC水平的机制扩展RLS （Delaney et al., 2011）。此外，在过去几年中，细胞大小在衰老中的潜在作用再次浮出水面，并重新引发了肥大可能参与衰老发生的争论（Demidenko & Blagosklonny, 2009a, b； Demidenko等人，2009a, b； Yang等人，2011）。具体而言，基于酵母和哺乳动物细胞的新证据，需要重新评估细胞大小和/或肥大在决定细胞寿命方面没有作用的结论（Demidenko & Blagosklonny, 2008; Demidenko et al., 2009a, b; Yang et al., 2011）。这场争论的关键点在于细胞大小的增加和/或肥大是否实际上减少了RLS，或者仅仅与酵母的衰老有关。迄今为止，有四项实验支持衰老过程中细胞大小增加和/或肥大的致病作用（Egilmez & Jazwinski, 1989； Zadrag等人，2006；Zadrag- tecza等人，2008；Yang等人，2011）。首先，虽然最初的alpha因子实验表明，尽管尺寸增加，但RLS并没有减少（Kennedy et al., 1994），但后续实验得出了相反的结论（Zadrag et al., 2006; Bilinski et al., 2012）。其次，与ERCs的诱导类似，通过快速增加细胞大小来诱导肥大可以显著降低ssf1D长寿突变体的RLS （Yang et al., 2011）。由于用于诱导肥大的条件相对严峻，这些实验不排除其他机制（例如染色体外rDNA环（ERCs）的增加，rDNA不稳定或蛋白质聚集体的快速积累）。然而，这似乎不太可能发生在3-5小时的诱导。尽管如此，这些观察结果引发了最近关于细胞大小和/或肥大在酵母衰老中的潜在作用的争论（Henderson & Gottschling, 2008； Bilinski等，2012a, b； Ganley等，2012;Kaeberlein, 2012）。支持细胞大小和/或肥大在衰老中起作用的假说的批评者提出了三个主要的争论点，详细如下：(1)肥大可能只与衰老细胞有关；(2)缺乏细胞尺寸减小延长寿命的证据；(3)并非所有的长寿细胞都是小的，反之亦然。在当前的衰老范式下，RLS被认为可以在子细胞中完全再生（Sinclair et al., 1998a, b; Henderson & Gottschling, 2008）。换句话说，中年母亲的女儿出生时应该拥有完整的预期寿命。一个例外是，非常高龄的母亲所生的女儿体型较大，RLS显著缩短（Johnston, 1966； Egilmez等人，1989；Kennedy等人，1994）。由此推论，肥大可能只与衰老细胞有关。然而，即使细胞大小适度增加，处女的寿命也会缩短（肯尼迪）
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 (eg 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