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PERSPECTIVE

Sir2 links chromatin silencing, metabolism, and aging

1Leonard Guarente

Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139 USA

Aging is manifested by a progressive decline in vitality at mating type loci (Rine and Herskowitz 1987) and telo- over time leading to death. Studies in budding yeast al- meres (Gottschling et al. 1990), and SIR2, but not SIR3 or low aging to be followed in individual pedigrees of cells, SIR4, is required for silencing in the rDNA (Bryk et al. that is, those of mother cells, consequent to many 1997; Smith and Boeke 1997). Silencing causes a more rounds of cell division (Mortimer and Johnston 1959). closed, inaccessible regional chromatin structure, as as- These studies have led to the general conclusion that the sayed by various probes of DNA accessibility (Loo and silencing protein Sir2 is a limiting component of longev- Rine 1994; Bi and Broach 1997). Even though expression ity; deletions of SIR2 shorten life span and an extra copy of marker genes inserted into the rDNA is repressed, of this gene increases life span (Kaeberlein et al. 1999). silencing of rDNA transcription itself may be more mod- Recent studies have spurred interest in Sir2 as a candi- est, as continued ribosome synthesis is essential for date longevity factor in a broad spectrum of eukaryotic growth. The Sir proteins may also function in DNA re- organisms. SIR2 gene homologs have been found in a pair by nonhomologous end-joining (NHEJ) (Tsukamoto very wide range of organisms ranging from bacteria to et al. 1997; Boulton and Jackson 1998). In this regard, the humans (Brachmann et al. 1995). Moreover, a biochemi- Sir2/3/4 proteins and Ku relocalize from telomeres to cal activity of Sir2 likely responsible for chromatin si- sites of DNA breaks to aid in their repair by NHEJ (Fig. lencing, nicotinamide–adenine dinucleotide (NAD)-de- 1A) (Martin et al. 1999; Mills et al. 1999). A primary role pendent histone deacetylase, has recently been discov- of the Sir complex at telomeres therefore may be to pro- ered and shown to be broadly conserved (Imai et al. vide a reservoir of factors that can be mobilized for the 2000). In this review, I will briefly discuss silencing as it immediate repair of DNA damage. pertains to SIR2 and its relationship to aging. I will then The function of Sir2 in promoting longevity in yeast trace the studies that led to the discovery of the NAD- mother cells appears to relate to silencing in the rDNA. dependent histone deacetylase. I will next speculate how The stability of the 100–200 tandem copies of rDNA on the regulation of Sir2 by NAD could represent the link chromosome XII requires SIR2, as the frequency of re- between caloric intake and the pace of aging, which is combination at that locus increases about 10-fold in sir2 widely observed in many organisms (Weindruch et al. mutants (Gottlieb and Esposito 1989). One of the prod- 1986). Finally, I will present a speculative model of how ucts of rDNA recombination is extrachromosomal a gradual disruption in chromatin silencing may occur rDNA circles (ERCs) (Fig. 1B), which, once formed, rep- and how such a change may cause aging. licate and segregate preferentially to mother cell nuclei (Sinclair and Guarente 1997). ERCs thus accumulate in mother cells as they grow older and ultimately trigger Maintenance of chromatin silencing and genome senescence. At least one function of Sir2 in yeast longev- stability by Sir2 ity, therefore, is to forestall the appearance of the first rDNA circle in mother cells by creating a silenced chro- Silencing of genomic DNA was first observed by repres- matin structure. sion of genes near certain translocation breakpoints in Silencing requires particular lysines in the extended Drosophila (for review, see Wakimoto 1998). Studies in amino-terminal tail of histones H3 and H4 (Thompson et Drosophila and yeast have led to the identification of al. 1994; Hecht et al. 1995; Braunstein et al. 1996). These factors that act in trans to mediate silencing. Among and other lysines of the tail are acetylated in active chro- these are the proteins encoded by the yeast SIR genes, matin but deacetylated in silenced chromatin (Braun- which are responsible for silencing at repeated DNA se- stein et al. 1993, 1996). The deacetylated histones evi- quences in yeast: mating type loci, telomeres, and the dently can fold into a more compact, closed nucleosomal rDNA. SIR2, SIR3, and SIR4 are all required for silencing structure (Luger et al. 1997). These considerations led to the suggestion that Sir2 could be a histone deacetylase. Further evidence for this claim arose from the global 1E-MAIL [email protected]; FAX (617) 253-8699. deacetylation of yeast histones observed when Sir2 was

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Guarente

Figure 1. Functions of Sir2 in yeast. Sir2 mediates silencing at telomeres, along with Sir3, Sir4, and Ku, (A) and at the re- peated rDNA (B) without these other fac- tors. Telomeric proteins respond to DNA double-strand breaks (DSBs) by moving to sites of damage in S-phase in a pathway requiring MEC1, RAD9, RAD53.Inasir2 mutant, homologous recombination in the rDNA increases leading to more ERCs. overexpressed (Braunstein et al. 1993). However, at- Because the deacetylase activity of Sir2 occurs prefer- tempts to demonstrate a histone deacetylase activity by entially on histone residues that are essential for silenc- Sir2 in vitro initially met with failure. ing, we infer that it is this activity, rather than the ADP– ribosyltransferase, that triggers silencing in vivo. Con- sistent with this claim, a mutation of Gly-270 of Sir2 to Sir2 is a conserved NAD-dependent histone deacetylase Ala reduces the ADP–ribosyltransferase by 93%, but re- duces the deacetylase activity by only 20% and still can Unlike SIR3 and SIR4, the SIR2 gene is broadly con- function in silencing, repression of rDNA recombina- served in organisms ranging from bacteria to humans tion, and extension of life span (Imai et al. 2000). Thus, (Brachmann et al. 1995). Studies on the bacterial homo- Sir2 is an NAD-dependent histone deacetylase that may log, cobB, led to the conclusion that this gene could sub- link metabolism and silencing in vivo (Fig. 2). The role of stitute for another bacterial gene, cobT, in the pathway the ADP–ribosyltransferase in vivo is still not clear, but of cobalamin synthesis (Tsang and Escalante-Semerena this activity is evidently separable from the deacetylase, 1998). cobT was known to encode an enzyme that trans- as a known inhibitor of mono-ADP–ribosyltransferases ferred ribose–phosphate from nicotinic acid mono- selectively inhibits the one activity of Sir2 and not the nucleotide to dimethyl benzimidazole. Thus, it seemed other (Imai et al. 2000). The ADP–ribosyltransferase may possible that Sir2 proteins might be equipped to catalyze turn out to be important to the function of Sir2 in DNA a related reaction at the nicotinamide–ribose bond in repair, as nuclear mono- and poly-ADP–ribosyltransfer- NMN and perhaps nicotinamide-adenine dinucleotide ases have been associated with DNA repair in mamma- (NAD), in the latter case resulting in transfer of ADP– ribose. Indeed, it was shown by Frye (1999) that Sir2 proteins from bacteria, yeast, or mammals were able to transfer 32P from NAD to a protein carrier, suggesting that they were ADP–ribosyl transferases. Subsequent work proved that Sir2 could, in fact, transfer ADP–ri- bose, albeit in a reaction that proceeds only weakly in vitro (Tanny et al. 1999). This latter study led to the proposal that the ADP–ribosyltransferase activity of Sir2 was essential to the in vivo function of silencing. In studying this ADP–ribosyl transferase reaction, we noticed that peptides of the amino-terminal tails of his- tone H3 or H4 could accept 32P from NAD, but only if the peptides were acetylated. Using acetylated H3, we separated the Sir2-modified product by chromatography and found by mass spectrometry that the molecular weight of the product was actually smaller by 42, indi- cating that the major modification catalyzed by Sir2 was deacetylation and not ADP ribosylation (Imai et al. Figure 2. Sir2 is an NAD-dependent histone deacetylase. The 2000). When NAD was omitted, no deacetylation by Sir2 deacetylation of lysines in the amino-terminal tails of histones occurred. NADH, NADP, or NADPH could not substi- H3 and H4 in nucleosomes (NUC) is proposed to convert active tute for NAD in this reaction. The weak ADP–ribosyl- to silenced chromatin. Sir2 is stimulated to carry out this reac- transferase reaction did not generate sufficient levels of tion by NAD, the available levels of which are likely coupled to product to allow detection by this physical method. the metabolic rate of cells.

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Sir2, chromatin, and aging lian cells (Kreimeyer et al. 1984; Pero et al. 1985; Meyer carbon flow through glycolysis would be high (Fig. 3A). and Hilz 1986). The glycolytic enzyme glyceraldehyde-3-P-dehydroge- nase (GAPDH) uses NAD, and the resulting NADH is recycled by the delivery of electrons to oxygen via the Is Sir2 a link between metabolic rate and aging? electron transport chain or, if oxygen is scarce, to acetyl- One of the most consistent observations in aging is the CoA to generate fermentation products. Thus, a substan- link between metabolic rate and the pace of aging (Wein- tial portion of the NAD pool may be recruited by this druch et al. 1986). Thus, if the metabolic rate of an or- high flow of carbon through gylcolysis. In contrast, when ganism is slowed down, for example, by lowering caloric calories are restricted, the flow of carbon through glycol- intake or by lowering ambient temperature for cold- ysis is low (Fig. 3B). Under these conditions more carbon blooded animals, life span is significantly extended is fully oxidized to CO2 via the enzymes of the TCA (Finch 1990). Interestingly, this link breaks down in cycle in mitochondria, which also use NAD with the comparisons between organisms. For example, rodents resulting NADH recycled via the electron transport and bats have comparable metabolic rates, yet bats live chain. However, because the carbon flow is much lower up to 10-fold longer. Thus, each species appears to have when calories are restricted, less NAD may be siphoned a predetermined rate of aging that is further regulated by from the common pool, leaving more for other NAD- the rate of metabolism integrated over the life time. binding proteins, including Sir2. In conclusion, I suggest Calorie restriction appears to be efficacious in a wide that Sir2 proteins may link metabolic rate to the pace of range of organisms, including rodents (Weindruch et al. aging by sensing NAD levels and generating the man- 1986), worms (Lakowski and Hekimi 1998), yeast (Mull- dated level of chromatin silencing. er et al. 1980), and probably primates (Roth 1999). There How might a loss of silencing cause aging? are no data yet pertaining to humans. In addition to pro- moting longevity, a nutritious yet calorie-restricted diet Models relating loss of silencing to aging have been de- gives rise to robust health and a high level of motor ac- scribed in yeast (Kennedy et al. 1995) and in mammalian tivity in experimental animals. The billion dollar ques- cells (Howard 1996; Villeponteau 1997; Imai and Kitano tion is: What is the mechanism by which calorie restric- 1998). In yeast, one effect of Sir2-mediated silencing is a tion increases life span? One school of thought relates to repression of recombination in the rDNA (Fig. 4). This the possible link between oxidative damage by reactive repression of genome instability delays the formation of oxygen species (ROS) and aging (Harman 1981). By this ERCs, which will ultimately lead to the demise of aging reckoning, lowering calories simply lowers the produc- mother cells. However, there is no good evidence that tion of ROS in mitochondria and thus slows aging. A ERCs, or for that matter any extra DNA, accumulates in different view is that calorie restriction provokes a radi- aging metazoan cells. Does this mean that the yeast cal shift in the metabolic strategy in cells, which some- model for aging bears no relevance to aging in higher how favors longevity. Gene-array analysis in calorie-re- organisms? Not necessarily. The generation and accu- stricted mice shows altered expression of ∼2% of genes, mulation of ERCs may be viewed as the molecular read- many involved in some aspect of cellular metabolism out of a breach in genomic silencing that leads to aging (Lee et al. 1997), suggesting that a simple shift in cellular in yeast. However, I imagine that in other organisms metabolism may favor longevity. different read-outs are possible. The most obvious of In this regard, the fact that the histone deacetylase these is the inappropriate gene expression that would activity of Sir2 is driven by NAD and thus linked to result from a loss of silencing (Fig. 4). cellular metabolism is quite provocative. Might Sir2 pro- Although we do not know the targets of Sir2 silencing teins offer an explanation of how calorie restriction regu- in the genomes of multicellular organisms, Sir2 proteins lates longevity? If calorie restriction were to increase the may help demarcate active and inactive regions that de- levels of available NAD, then Sir2 activity would likely termine cell type. This surmise is strengthened by the be enhanced, resulting in greater silencing and poten- finding that a murine Sir2 also can function as an NAD- tially a longer life span. It is likely that Sir2 is in com- dependent histone deacetylase (Imai et al. 2000). Any petition with other NAD-using enzymes in cells for the gradual loss in silencing would lead to an erosion of the dinucleotide. When cells have high levels of calories, the required chromatin landscape, perhaps resulting in an

Figure 3. Possible role of NAD as mediator of calo- rie restriction. In calorie excess (A), glucose is oxi- dized at a high rate by glycolytic enzymes, which sequesters a portion of the available NAD from the common pool. Thus, Sir2 activity is relatively low. In calorie restriction (B) the flow of carbon through glycolysis and the TCA cycle is low, thus increasing available NAD, elevating Sir2-promoted silencing, and promoting a longer life span.

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How might silencing be lost over time? If, in fact, a loss of silencing can cause aging, it begs the question of how this loss might occur. Here, I present a speculative model that takes into account the second function of Sir2 proteins—as mediators of DNA repair. I suggest that Sir2 is chronically recruited from silenced chromatin to sites of DNA damage to aid their repair (Fig. 5). After the DNA has been repaired, Sir2 would return to its prior residence. However, if this mobiliza- tion and resetting of Sir2 proteins were <100% efficient, Figure 4. How Sir2- silenced chromatin might promote lon- there would be a gradual erosion in the integrity of si- gevity. In yeast, silencing in the rDNA represses recombination lenced chromatin over time. The image that comes to (genome instability) and thus extends life span. In general, si- mind is the futility of trying to repack what once was a lencing also prevents inappropriate gene expression, which may perfectly packed suitcase at the end of a trip. As dis- be relevant to the maintenance of differentiated cells in meta- cussed above, any erosion in silencing could lead to in- zoans and the extension of life span. appropriate gene expression and phenotypes of aging. This view unites several features of aging. Impor- tantly, the model applies equally well to cells that are alteration of phenotype such as dedifferentiation (Ono mitotic, such as skin, intestine, blood, etc., as to cells and Cutler 1978) or even cell death. These changes may that are postmitotic, such as neurons and muscle. In the play a causative role in the progressive deterioration of case of dividing cells, much of the DNA damage is likely vitality during aging. generated because of errors that occur during DNA rep- Is there any evidence that changes in chromatin struc- lication. Mutations in factors of the replication of repair ture may lie at the heart of aging in mammals? The clon- machinery in diseases such as Werner syndrome (Yu et ing of animals by the “reprogramming” of adult cell nu- al. 1996), Cockayne syndrome, and ataxia telangiectasia clei in oocytes (Wilmut et al. 1997; Wakayama et al. (Savitsky et al. 1995) may exaggerate the generation of 1998) may be relevant in this regard. Studies in sheep and DNA damage and give rise to the apparent acceleration mice, although still rather preliminary, give no evidence of aging, especially in organs with mitotic cells. In post- that the clones will show accelerated aging or a reduced mitotic cells, DNA damage may be generated by agents life span. Assuming that the cloning process does not such as ROS. In the case of muscle or brain cells, the rate strongly select for “young” cells in the adult soma, any of respiration is especially high, which may favor the aging-related changes that have occurred in adult cells production of ROS, thereby triggering DNA damage. are reversed by the reprogramming in oocytes. This re- Can anything be done to slow the aging process? The programming may well be the resetting of the chromatin model outlined above suggests that interventions result- structure to a zygotic landscape, which, in turn, resets ing in an increase in the capacity of Sir2 proteins to sus- the aging clock. Any irreversible changes in the DNA of tain silencing ought to slow aging. In yeast, an extra copy adult soma, for example, deletions or other mutations, of SIR2 does slow aging and increase life span. It should could not be reset by cloning and are therefore not likely be possible to carry out similar tests in experimental causes of aging. That said, it has been repeatedly ob- animals, such as Caenorhabditis elegans and mice. In served that DNA mutations do occur over time in adult humans the task is more formidable. Any novel Sir2 ago- soma (Melov et al. 1995; Vijg 2000). These mutations nists, for example, molecules that would enter cells and may not contribute to any aging phenotype, but it is mimic the effect of NAD on Sir2, might offer the prom- possible that they will cause other anomalies in cloned ise of long-term intervention to slow the aging process. animals, such as higher cancer rates. Although it seems unlikely that any drastic extension in

Figure 5. Model for loss of silencing over time in aging. Sir2 is present at silenced chromatin and can be recruited to sites of DNA damage, which occurs chronically over a lifetime. Damage may be in- duced during DNA replication in dividing cells, and may be exacerbated by mutations in DNA re- pair functions, such as the Werner DNA helicase. ROS, especially in nondividing cells, may also con- tribute to DNA damage. If the resetting of silenced chromatin were <100% efficient, there would be a gradual erosion of silencing, which may lead to in- appropriate gene expression or genome instability.

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Sir2 links chromatin silencing, metabolism, and aging

Leonard Guarente

Genes Dev. 2000, 14: Access the most recent version at doi:10.1101/gad.14.9.1021

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