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GUEST EDITORIAL |
Biology of Aging, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
Address correspondence to Felipe Sierra, PhD, Biology of Aging, National Institute on Aging, National Institutes of Health, 7201 Wisconsin Ave., Suite 2C231, Bethesda, MD 20892. E-mail: sierraf{at}nia.nih.gov
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Free radicals provide a generally accepted explanation for age-related decline in tissue function. However, the free radical hypothesis does not provide a mechanistic course of action to explain exactly how damage to macromolecules translates into the recognizable pathophysiology of aged organisms. Recent advances in the fields of DNA damage and cellular senescence point towards a substantial role for the DNA damage response, rather than DNA mutations per se, in the genesis of cellular and/or tissue damage. Furthermore, several studies suggest that protein damage can be at least as important as DNA damage in bringing about the aging phenotype. Here we propose that a "protein damage response," namely the ER/UPR (endoplasmic reticulum/unfolded protein) stress response is likely to play an important role in the aging process.
The cellular response to irreparable DNA damage is better understood than is the response to protein damage. Point mutations in DNA, either as a result of damaging insults or errors in replication, do not often activate a cellular response. However, more severe damage (for example, genomic instability brought about by double-stranded breaks or bulky adducts) leads to activation of a p53-dependent response, which can result in apoptosis or senescence (4). There are accumulating data in the literature suggesting that premature aging is not a sine qua non result of increased DNA damage, but rather, premature aging only occurs in those models where repair is inadequate and the cellular response to DNA damage has been activated (see below). There are now also data that suggest that damage to proteins might be relevant to aging (5), and it is therefore tempting to suggest that, in this case too, aging will ensue only if a cellular response to that damage is activated. Here we propose that the ER or UPR stress response (Endoplasmic Reticulum or Unfolded Protein Response, respectively) (6) could play this role, and thus be central to the development of the aging phenotype. As in the case of the DNA damage response, activation of the ER/UPR stress response by damaged proteins can also lead to both loss of cellular function and, if overwhelmed, apoptosis (Figure 1).
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DNA is believed to suffer different types of damage, such as breaks, abasic sites, and base lesions. It has been estimated that at least 2,000–10,000 purine bases are turned over per day per cell (7). This creates an enormous burden, and consequently, a complex and interwoven system of DNA repair enzymatic activities exists within each cell, to reverse such damage. It has been estimated that hundreds of genes in the human genome are directly devoted to DNA repair mechanisms, with many more ancillary factors suspected (8). The genome is kept intact by two major mechanisms: caretakers and gatekeepers (9). The functions of caretakers are to ensure that the DNA is not damaged and, if it is, to get it repaired. Caretakers include enzymes that scavenge reactive oxygen species (ROS) and DNA repair mechanisms. However, if the caretakers fail and DNA gets irreparably damaged, then gatekeepers come into play, and they "decide" the fate of the affected cell as a whole. Classical gatekeepers include the tumor suppressor proteins p53 and pRB. Gatekeepers are not activated by point mutations; therefore, point mutations do not engage a cellular response. However, when gatekeepers sense that the damage is irreparable, they activate a cellular response (either apoptosis or senescence), which effectively removes the affected cell from the pool of proliferating cells (4).
There are considerable data indicating that, if a cellular response to damage is not activated, then cells can withstand a significant amount of damage to DNA without the organism showing signs of premature aging (10). Indeed, in most of the mouse models where caretaker functions have been inactivated, an increased level of DNA mutations has been observed as expected, but the mice fail to display an accelerated aging phenotype. For example, Xpc–/– mice accumulate up to 30-fold higher levels of DNA mutations than do their wild-type counterparts, yet there is no effect on their life span (11). A similar, though less dramatic result has been observed in the case of scavenging proteins. For example, Van Remmen and colleagues (12) reported that the SOD2+/– mouse suffers a 3-fold to 4-fold increase in DNA mutations, with no detectable effect in life span. Because these animals indeed display a significant increase in DNA damage, it cannot be argued that the effect of the gene knockout is being counterbalanced by a partly redundant mechanism: There is a considerable accumulation of unrepaired mutations that has no deleterious effect on life span. There are exceptions, including the Ku86–/– mouse (13), the XPDTTC mouse (14), and more recently, a model in which catalase was directed to the mitochondria (15). In these cases, the expected changes in life span were observed (decrease in the two former, increase in the latter). The mechanisms that explain the differences between the different models still need to be unraveled. In contrast, mouse models in which the activity of gatekeepers (including telomerase, Wrn, Blm, ATM, or p53) has been manipulated do generally display an accelerated aging phenotype (16–20). In the cases of telomerase, Wrn, Blm, and others, the gene knockout results in generalized genomic instability, including not only double-stranded breaks, but also telomere shortening and/or stalled replication or transcription complexes, both of which appear to be interpreted by the cell as an unrepaired double-stranded break. As previously mentioned, this type of damage leads to activation of a response that culminates in cellular senescence or apoptosis (4). From these data, we must conclude either that genomic instability (but not mutations) plays a role in aging, or that longevity is related to the cellular response of the cell to such DNA damage.
CELLULAR RESPONSE TO PROTEIN DAMAGE
The integrity of the cellular proteome can also be viewed as being dependent on caretakers and gatekeepers. Caretakers would perform all the activities that prevent protein damage (ROS scavengers and chaperones, for example) or take care of the damaged proteins (proteolysis and protein repair mechanisms). In contrast, gatekeepers would function to assess this damage and decide whether it can be repaired. In analogy to genome gatekeepers, the ER/UPR response can be viewed as a gatekeeper function for proteins, because its activation can, under certain circumstances, lead to programmed cell death (6).
The ER/UPR stress response is a cell-protective mechanism that can be triggered by accumulation of damaged or misfolded proteins in any cell compartment, including the nucleus (21). In young organisms at least, accumulation of damaged proteins activates a series of sensors, including PERK, IRE1, and ATF6 (reviewed in 6). Activation of these pathways converges in the activation of ER chaperones, including several glucose-regulated proteins (GRP), primarily GRP78 (22). The overall effects are: (i) to increase the levels of available chaperones, (ii) to reduce the rate of protein synthesis, and (iii) to activate several protein degradation pathways. Altogether, these effects result in an alleviation of the stress produced by the misfolded proteins (23). However, the need for the cell to devote resources to protect itself comes at the price of a partial disregard for its more differentiated functions. This switch is mediated by the overall decrease in the rate of new protein synthesis, which occurs concomitantly with the upregulation of genes encoding chaperones. This temporary change in priorities results in saving the cell from deleterious environmental conditions, and therefore saving the tissue from permanent loss of function (21). However, this shift also means that the ER/UPR stress response is even better equipped than is the DNA damage response to produce tissue-wide dysfunction, because its activation results in loss of differentiated tissue functions even if damage is not overwhelming enough to activate the apoptosis or senescence pathways.
Because the ER stress response is a transient protective mechanism that leads to the re-establishment of proper homeostasis, under most circumstances, activation of the ER stress response should not lead to the progressive deterioration observed during aging. However, it is possible that during aging, decreased efficiency of the response, or other factors including persistent insults or a decreased capacity to activate proteolytic pathways (24,25) might lead to a sustained ER stress response. This sustained response could be directly responsible for the loss of tissue function, through the persistent diversion of cellular efforts away from differentiated activities, as described above. Some additional facts about aging and the ER stress response become relevant at this point: (i) GRP levels increase with age, and the increase is rapidly reversed by diet restriction (26); (ii) Induction of heat shock protein (hsp) 70 family members by a variety of stressors is diminished in old organisms [reviewed in (27)]; (iii) Overexpression of hsp70 family members extends life span in Caenorhabditis elegans (28,29); (iv) One of the hallmarks of long-lived organisms is their increased resistance to oxidative as well as many other types of stress (30); and (v) Having said that, cells under severe stress do die! We propose that it is this cell death, in conjunction with the loss of functionality of the surviving cells, that is at the root of the age-related decline in tissue mass and function.
The main issue here is that stochastic DNA mutations or random damage to proteins or other macromolecules will not lead to a coordinated cellular response, and therefore, will not lead to the phenotype of accelerated aging. In contrast, activation of a programmed damage response will lead to a decrease in cell and tissue function that does not depend on which molecule was originally affected, and therefore is no longer idiosyncratic. Instead, all the cells subjected to the insult would have a concordant, preestablished response, which includes a decrease in differentiated functions (Figure 2).
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Conclusion
If aging is controlled not by how much damage an organism sustains, but rather, by its ability to respond to such damage, then it is reasonable to conclude that aging and longevity should be controlled genetically, at least in part. This prediction has been proven to be true in the last decade or so. A few more direct, testable hypotheses can be drawn from this proposal. For example, life span should be affected by genetic manipulation of GRP or heat shock proteins (28,29), as well as by manipulations that affect the equilibrium that dictates whether a challenged cell goes into apoptosis or senescence. Precise tuning of either the threshold or the overall activity of cellular responses such as the ER response should also correlate with life span in organisms of different species, or among members of a cohort. Another testable corollary is that apoptosis and/or senescence pathways should be activated in those mouse models which display accelerated senescence, but not in models where damage is increased, but longevity is not affected. Activation of these pathways has been shown in a subset of the models, but more research will be necessary before a general conclusion can be drawn.
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I thank Drs. Judith Campisi, Huber Warner, and Ueli Schibler for critical reading of the manuscript.
F
Decision Editor: James R. Smith, PhD
Received October 14, 2005
Accepted November 22, 2005
References
This article has been cited by other articles:
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  A. B. Salmon, A. A. S. Akha, R. Buffenstein, and R. A. Miller Fibroblasts From Naked Mole-Rats Are Resistant to Multiple Forms of Cell Injury, But Sensitive to Peroxide, Ultraviolet Light, and Endoplasmic Reticulum Stress J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2008; 63(3): 232 - 241. [Abstract] [Full Text] [PDF]
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D. Simar, D. Malatesta, S. Badiou, A. M. Dupuy, and C. Caillaud Physical Activity Modulates Heat Shock Protein-72 Expression and Limits Oxidative Damage Accumulation in a Healthy Elderly Population Aged 60 90 Years J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2007; 62(12): 1413 - 1419. [Abstract] [Full Text] [PDF]
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