Bay Area Aging Club – Panel discussion: Free radical theory of aging

(previous session)

At the end of the meeting, Martin Brand and Stuart Kim led a group discussion about the free radical theory of aging. Martin began the discussion by pointing out that “after 50 years, you would expect a theory to accumulate enough evidence to convince us that it’s true or false – but the fact that we’re still discussing it today means that hasn’t happened.” I’m paraphrasing slightly, but that’s the general idea.

Martin Brand (who doesn’t, by the way, adhere to this theory) started by summarizing the evidence in favor of FRTA:

• “50 million Frenchmen can’t be wrong” (i.e., there are lots of correlative experiments)
• SOD2 knockout is bad
• catalase overexpression is good

Stuart rejoined with some contradicting evidence:

• Superoxide dismutase protects against oxidative stress but has little effect on lifespan in mice
• Deletion of mitochondrial SOD extends lifespan in C. elegans
• High oxidative damage levels in the longest-living rodent, the naked mole-rat.

To the last of which, others answered:

• The naked mole rat isn’t suffering from a global increase in oxidative damage – rather, there are a small number of proteins with increased damage, which may represent antioxidant proteins protecting the rest of the cell
• There’s no evidence that naked mole rats increase damage with age, which is a more relevant metric

The first two pieces of Stuart’s contradicting evidence were more difficult to challenge. Some ideas:

• Overexpressing an antioxidant enzyme in the wrong subcellular compartment wouldn’t be predicted to have any effect on lifespan

Martin also asked questions about whether FRTA is even falsifiable, and lamented the absence of an alternative clear, single-sentence “singular” theory of aging.

No final resolution but on the balance it seems like the theory is on the ropes, as we’ve discussed here before.

 

Bay Area Aging Club – Session II: Sirtuins; telomeres

(previous session)

Matt Hirschey (Verdin Lab, UCSF-Gladstone): Lack of SIRT3 results in the metabolic syndrome. SIRT3 is a mitochondrial sirtuin (NAD+-dependent deacetylase) that is upregulated in liver upon fasting; knockout mice (SIRT3KO) are grossly normal but have trouble with lipid metabolism (specifically, beta-oxidation). Hershey identified several mitochondrial proteins involved in lipid oxidation that are deacetylated in response to fasting, in wildtype but not SIRT3KO. The knockouts are prone to developing obesity and metabolic syndrome with age.

Kate Brown (Chen lab, UC-Berkeley): Calorie restriction reduces oxidative stress by inducing SIRT3. Beginning with an invocation of the free radical theory of aging, and the observation that calorie restriction (CR) reduces oxidative stress, Brown asked whether the mitochondrial sirtuin SIRT3 could be involved in resistance to reactive oxygen species. She showed that CR induces SIRT3 expression, and that the SIRT3 protein deacetylates the mitochondrial antioxidant enzyme SOD2. Furthermore, consistent with Subhash Katewa’s talk in the first session, she demonstrated that CR reduces oxidative stress by switching from glucose to fatty acid oxidation, and that this switch requires SIRT3 activity.

(We’ve discussed SIRT3 before, most recently regarding its role as a tumor suppressor and also with respect to its relationship with exercise).

Ruth Tennen (Chua lab, Stanford): Insight into SIRT6 function at telomeres and beyond. Another member of the sirtuin family, SIRT6, is not localized to mitochondria but rather to telomeres, where it maintains telomeric chromatin in a healthy state and regulates the activity of the senescence-associated transcription factor NF-κB – for more background, see this previous post.) Tennen has shown that SIRT6 is involved in regulating the telomere position effect (TPE) – the silencing of gene expression caused by proximity to a telomere. The TPE has been implicated in age-related changes in gene expression: as telomeres shorten over time, telomere-proximal genes are aberrantly expressed — meanwhile, silencing factors are liberated to wander throughout the genome, repressing genes that should be turned on; similar logic has been applied to the relationship between DNA damage and transcriptional dysregulation.

Jue Lin (Blackburn Lab, UCSF): Telomere length maintenance and aging-related diseases. This talk described work that builds on significant progress, from this lab and others, demonstrating relationships between telomere length and stress, psychological outlook, and lifespan. Lin reviewed evidence that perceived stress is correlated with telomere length in white blood cells (consistent with previous results showing a relationship with intrusive thoughts). New-to-me data included a demonstration that people who increased omega-3 levels or made favorable lifestyle changes exhibited a slower rate of telomere shortening.

(next session)

 

Nature Insight: Ageing

Nature’s most recent “Insight” supplement is devoted to a topic near and dear to our hearts, even when spelled with that superfluous UK “e”: Ageing. From the introductory editorial:

Ageing, the accumulation of damage to molecules, cells and tissues over a lifetime, often leads to frailty and malfunction. Old age is the biggest risk factor for many diseases, including cancer and cardiovascular and neurodegenerative diseases. … Ageing research is clearly gaining momentum, as the reviews in this Insight testify, bringing hope that at some time in the future we will be able to keep age-related diseases at bay by suppressing ageing itself.

The five reviews are all by prominent scholars — many of whose work we’ve discussed here — and cover a wide range of subjects within gerontology and biogerontology:

• The genetics of ageing, Cynthia J. Kenyon
• Lessons on longevity from budding yeast, Matt Kaeberlein
• Linking functional decline of telomeres, mitochondria and stem cells during ageing, Ergün Sahin & Ronald A. DePinho
• Neural mechanisms of ageing and cognitive decline,
  Nicholas A. Bishop, Tao Lu & Bruce A. Yankner
• Biodemography of human ageing, James W. Vaupel

As always, Nature Insight supplements are free-access, so even if you don’t have access to a university subscription, you can still read these articles.

(For a previous aging-related Nature Insight on DNA repair, see here.)

 

Review Roundup #5

Here are the biogerontological reviews from the last month or so that I’ve found interesting and noteworthy. The field as a whole continues to massively overproduce review papers; by my totally unscientific estimate, these represent less than ten percent of the review abstracts that crossed my desk since Thanksgiving.

The last installment of review roundup can be found here. As always, each Review Roundup is guaranteed to contain at least one link to a review you will find highly educational, or your money back.

Comparative biogerontology:

A while back I attended a NAKFI meeting about aging. Along with a few others, I applied for (and got) a seed grant to use comparative zoology to study aging — in a nutshell, to study the various ways that nature has solved various problems that arise during aging, and see whether we might learn something that could be applied to enhancing human healthspan or lifespan.

The initial small grant funded a series of meetings, culminating in a large-scale gathering of scientist with wide expertise not only in biogerontology but also zoology, evolutionary biology, metabolomics, and other disparate fields. While this conference didn’t end up leading to the creation a single comprehensive Comparative Biogerontology Initiative, as some of my fellow applicants had hoped, it did provoke a great deal of excellent discussion. There are a few smaller-scale efforts currently underway, initiated by people who came together to talk about the original idea.

Two of the attendees of the big meeting have published reviews recently. I haven’t asked them personally but I am assuming that they’re discussing ideas that germinated at the CBI conferences.

• Insights from comparative analyses of aging in birds and mammals, Robert Ricklefs
• Methusaleh’s Zoo: How Nature provides us with Clues for Extending Human Health Span, Steven Austad

Gene regulation:

• Genetic, epigenetic and posttranslational mechanisms of aging, Robert et al.

Inflammation:

• Evolution of the human lifespan and diseases of aging: Roles of infection, inflammation, and nutrition, Caleb Finch
• Inflammaging (inflammation + aging): A driving force for human aging based on an evolutionarily antagonistic pleiotropy theory?, M. Goto

Mitochondria:

One of the authors of the first paper is Thomas Nyström, whose lab recently described the role of cell polarity in sorting protein aggregates preferentially into the mother cell during cell division. That story lacked a significant mitochondrial component, so this review is a nice complement to the primary study published earlier this year.

• Perspectives on the mitochondrial etiology of replicative aging in yeast, Ugidos et al.
• The mtDNA mutator mouse: Dissecting mitochondrial involvement in aging, Edgar & Trifunovic

Nuclear organization:

• Nuclear and Chromatin Reorganization during Cell Senescence and Aging – A Mini-Review, Shin et al.

Stem cells:

Leanne Jones, the senior author on this review, is one of the folks writing the proverbial book on the critical interactions between stem cells and the tissue microenvironment. Her lab uses the Drosophila gonad as a model system.

• Stem Cells and the Niche: A Dynamic Duo, Voog & Jones

 

RIP for MFRTA?

A prominent scholar of the CLK-1 story has called the coroner on the mitochondrial free radical theory of aging (MFRTA). From Lapointe & Hekimi:

When a theory of aging ages badly

According to the widely acknowledged mitochondrial free radical theory of aging (MFRTA), the macromolecular damage that results from the production of toxic reactive oxygen species (ROS) during cellular respiration is the cause of aging. However, although it is clear that oxidative damage increases during aging, the fundamental question regarding whether mitochondrial oxidative stress is in any way causal to the aging process remains unresolved. An increasing number of studies on long-lived vertebrate species, mutants and transgenic animals have seriously challenged the pervasive MFRTA. Here, we describe some of these new results, including those pertaining to the phenotype of the long-lived Mclk1 +/− mice, which appear irreconcilable with the MFRTA. Thus, we believe that it is reasonable to now consider the MFRTA as refuted and that it is time to use the insight gained by many years of testing this theory to develop new views as to the physiological causes of aging.

MFRTA recently turned 50, and consequently has received a lot of attention lately; q.v. this review and this retrospective by Denham Harman, the originator of the theory. The thesis of most pieces seems to be that the theory hasn’t been demonstrated to explain the bulk of age-related decline, but that there’s still life in the idea. In contrast, the authors of this review argue that the relevant experiments have been performed and that the theory has been falsified — in other words, we’ve done our scientific duty and it’s now time to move on.

I doubt very much that this article will put a permanent end to the controversy. Data reported fairly recently have breathed new life into oxidative theories in general and the MFRTA in particular. While these authors contend that the CLK-1 mouse mutant contradicts the underlying mechanisms of the MFRTA, other recently reported work on this pathway supports the claim that inhibiting mitochondrial respiration delays aging, a key prediction of MFRTA.

Furthermore, if mitochondrially generated oxidative radicals are truly not playing a causative role in aging, it becomes much harder to explain how mitochondrially targeted antioxidants can extend lifespan in mammals.

Lapointe, J., & Hekimi, S. (2009). When a theory of aging ages badly Cellular and Molecular Life Sciences DOI: 10.1007/s00018-009-0138-8

 

Sexing up the soma: Long-lived mutants express germ line genes in somatic tissues

We are all descendents of an unbroken line of cell divisions, dating back to the last common ancestor of all life on Earth. At some point, long after our lineage had acquired features like nuclei and mitochondria, a less distant ancestor stumbled on a major innovation: it grew a body, bringing with it the advantages of cell and tissue specialization.

For many multicellular organisms, this specialization included a distinction between the mortal cells (the “soma”) and the potentially immortal cells (the “germ line”) that are capable of participating in the creation of new organisms. When you look at us, most of what you see is soma — the germ line is safely tucked away in the gonad, which is (usually) itself tucked away someplace safe.

But both the germ line and soma are made of cells. How is it that the soma is mortal while the germ line is, for practical purposes, immortal?

The disposable soma theory of aging begins from the premise that an organism has access to a finite amount of resources (broadly, energy and matter), and that it must distribute these resources in a way that maximizes reproductive fitness. First dibs goes to the germ line (without which it doesn’t matter, in a fitness sense, what becomes of the rest of the organism) and the rest gets divided among the cells of the soma.

For the moment, all we really need to take away from this model is that the germ line and soma are maintained in different ways, either in quality or extent. The germ line is doing something differently than the soma, the upshot of which is that the germ line is immortal. (A strict interpreter of the theory would presume that this “something” is resource-intensive, so that it wouldn’t be possible to apply the strategy to the soma. It’s also possible, however, that it’s simply inconsistent with optimal somatic functions — e.g., that making a muscle the best muscle it can be requires that myocytes not partake of the germ line strategy for immortality, for some structural reason that has nothing to do with resource allocation per se.)

One oh-wow corollary of this model is that if somatic cells could be made more like germ line cells, they would live longer. This prediction has a deliciously outrageous quality — yet is so simple that upon first hearing it, I reached for the nearest journal with the intention of rolling it up and smacking myself repeatedly on the forehead. Fortunately, there was a copy of Nature handy.

To be honest, it didn’t really happen that way. That copy of Nature contained the very article that introduced me to this concept: Curran et al. have shown that in long-lived mutants of the worm C. elegans, somatic tissues start acting like germ line cells:

A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants

Unlike the soma, which ages during the lifespan of multicellular organisms, the germ line traces an essentially immortal lineage. Genomic instability in somatic cells increases with age, and this decline in somatic maintenance might be regulated to facilitate resource reallocation towards reproduction at the expense of cellular senescence. Here we show that Caenorhabditis elegans mutants with increased longevity exhibit a soma-to-germline transformation of gene expression programs normally limited to the germ line. Decreased insulin-like signalling causes the somatic misexpression of the germline-limited pie-1 and pgl family of genes in intestinal and ectodermal tissues. The forkhead boxO1A (FOXO) transcription factor DAF-16, the major transcriptional effector of insulin-like signalling, regulates pie-1 expression by directly binding to the pie-1 promoter. The somatic tissues of insulin-like mutants are more germline-like and protected from genotoxic stress. Gene inactivation of components of the cytosolic chaperonin complex that induce increased longevity also causes somatic misexpression of PGL-1. These results indicate that the acquisition of germline characteristics by the somatic cells of C. elegans mutants with increased longevity contributes to their increased health and survival.

Just to be clear: the somatic tissues of the long-lived mutants had not actually transformed into germ line cells as such, nor were the mutant worms festooned with extra gonads (though admittedly, that would be totally awesome). Rather, the somatic tissues exhibited gene expression patterns ordinarily found only in the germ line.

On the correlation vs. causation issue: The authors showed, using RNAi knockdowns, that the germ line-restricted genes were required for the longevity enhancement due to the mutation in daf-2 (worm insulin/IGF). There’s a bit of a wrinkle: in wildtype animals, blocking these same genes actually resulted in an increase in lifespan. How to explain that? The proffered rationale is that in the wildtype, germ line-restricted genes are only present in the germ line. Knocking them down has no effect on somatic tissue, but might reduce the activity of germ line cells; it’s been known for some time that ablating part of the gonad has life-extending consequences in wildtype animals.

The critical observation, in any case, is that the germ line genes are turned on in daf-2 mutants, and this activation is necessary in order for daf-2 mutation to extend lifespan.

Next questions, in rough order of difficulty:

1. Does the soma-to-germ line transition occur in other long-lived mutants, or in calorie restricted animals?
2. By what mechanisms are the germ line-restricted genes extending the somatic lifespan?
3. Will this finding generalize to other metazoans?
4. Do the germ line genes expressed in daf-2 soma contribute to germ line immortality?

Curran, S., Wu, X., Riedel, C., & Ruvkun, G. (2009). A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants Nature DOI: 10.1038/nature08106

 

Did aging evolve to prevent epidemics?

How did aging evolve? Some evolutionary theories invoke tradeoffs between maintenance/repair and reproduction. Others postulate that genes that cause age-related decline can be positively selected, so long as these same genes confer a fitness advantage early in life.

A common feature of these theories is that they operate at the level of the individual organism, rather than the species. Models based on group selection usually have logical problems. For example, suppose that aging evolved in order to eliminate post-reproductive old organisms to preserve resources for the reproductively competent young. This is circular: Why are the old organisms were post-reproductive in the first place? i.e., the model presupposes some age-related decline in organ system function in order to rationalize the evolution of aging.

OK, so suppose that the old remain fertile, but eliminate themselves to avoid competition with their own offspring; reproductive senescence then evolves later since there’s no positive selection pressure for maintaining reproductive function over the long term. Problem: What’s the point? If both old and young are making copies of the same genes, there’s no fitness advantage in eliminating the old — especially in light of the fact that most of the offspring’s competition would be coming not from their own parents and grandparents but from more distantly related members of the same species. (And in sexual organisms, you are a better copy of your own genes than your offspring, who have only half of your alleles. Far better to stick around and show the kids how it’s done, than ride off into the sunset to clear the path for these dilutions of oneself.)

Group selection of aging is also vulnerable to “defectors” — mutants who take advantage of the situation to spread their own selfish genes. Suppose that there is some species-level advantage to aging, such that it emerges as a positively selected trait. As organisms age, they actively decrease their own viability in such a way that they have an increased mortality. The species benefits (somehow) at the cost of the individual fitness of these “cooperators.” But then along comes a defector mutant, who doesn’t age and continues to reproduce while the cooperators are pushing up the daisies. Unless the species-level advantage is overwhelming, it’s clear that the defector trait will spread within the population.

Ultimately, then, the reason why group selection models don’t satisfactorily explain the evolution of aging is that it’s hard to imagine a scenario in which a species-level advantage conferred by aging could outweigh the organism-level advantage conferred by not aging.

Such a scenario might now have been imagined. Mitteldorf and Pepper postulate that senescence could have evolved in order to prevent the spread of disease epidemics in populations:

Senescence as an adaptation to limit the spread of disease

Population density is a robust measure of fitness. But, paradoxically, the risk of lethal epidemics which can wipe out an entire population rises steeply with population density. We explore an evolutionary dynamic that pins population density at a threshold level, above which the transmissibility of disease rises to unacceptable levels. Population density can be held in check by general increases in mortality, by decreased fertility, or by senescence. We model each of these, and simulate selection among them. In our results, senescence is robustly selected over the other two mechanisms, and we argue that this faithfully mirrors the action of natural selection. This picture constitutes a mechanism by which senescence may be selected as a population-level adaptation in its own right, without mutational load or pleiotropy. The mechanism closely parallels the ‘Red Queen hypothesis’, which is widely regarded as a viable explanation for the evolution of sex.

OK, so, how might this work?

Epidemiology is, by definition, a population-level issue, and there’s already precedent for selection pressure based on disease susceptibility guiding evolution at the species level (e.g., the diversity of major histocompatibility loci).

The trick is to get the pressures at the individual and group levels to point in the same direction: If I (an organism) am more susceptible than average to a given disease, and that susceptibility has a genetic component, then my closest relatives (who share most of my genes) are likelier than the general population to be susceptible as well. Therefore, my continued existence poses a risk for my progeny, because I represent one more potential host for a pathogen that might infect them – potentially killing us all and ending the line altogether. One way to deal with that problem is to eliminate hosts, and the authors’ model shows that senescence is a reasonable way to achieve that end.

Mitteldorf, J., & Pepper, J. (2009). Senescence as an adaptation to limit the spread of disease Journal of Theoretical Biology DOI: 10.1016/j.jtbi.2009.05.013

 

Found in (mis)translation: A novel role for protein synthesis fidelity in aging

The idea that translation fidelity might play a role in aging dates back at least as far as 1963, when Leslie Orgel proposed the “error catastrophe” theory of aging: in this model, mistranslation of the translational machinery creates a feedback loop that leads to further translation errors, ultimately causing loss of cell viability. From the Science of Aging Timeline:

Orgel considers two types of proteins: those involved in metabolism, and those involved in information processing. For metabolic proteins, translational error isn’t a long-term problem for the cell, since a malfunctioning protein is simply one of many. Likewise, for translational errors causing loss of function in information processing proteins: the error isn’t heritable, and a small decrease in the efficiency of gene expression is unlikely to pose a serious problem.

However, information processing proteins can be altered in another way: by mutations that decrease the fidelity with which they process or propagate genetic information. Lower-fidelity transcription and translation will result in more mutations. This is the core of Orgel’s idea: “errors which lead to a reduced specificity of an information-handling enzyme lead to an increasing error frequency. Such processes are clearly cumulative and…in the absence of an imposed selection for “accurate” protein-synthesizing units, must lead ultimately to an error catastrophe; that is, the error frequency must reach a value at which one of the processes necessary for the existence of viable cell becomes critically inefficient.”

The logic of the feedback loop is compelling, but the theory suffered for lack of experimental verification. While there is still some controversy over whether error catastrophe has received a full and fair experimental test, the consensus appears to be that while error catastrophe can take place under some systems (e.g., viral replication in the presence of drugs that reduce polymerase fidelity), this phenomenon does not play a role in mammalian aging: the measured values of the relevant parameters (basal translation error rates; the likelihood that a given error will result in further alteration to translation fidelity; protein lifetimes; etc.) appear to be such that the feedback loop doesn’t actually occur.

The error catastrophe theory is still an important waypoint in the evolution of theories of aging, and it has had tremendous influence in other areas within biogerontology. For example, similar logic has been applied to the role of autophagy in aging, where the feedback loop is called the garbage catastrophe.

And even if the feedback-loop logic doesn’t hold up to experimental scrutiny, recent findings have revealed that there may nonetheless be a relationship between protein translation fidelity and aging. Writing in PLoS ONE, Silva et al. report that in yeast, increasing the rate of translation errors might increase the activity of the longevity assurance gene SIR2:

The Yeast PNC1 Longevity Gene Is Up-Regulated by mRNA Mistranslation

Translation fidelity is critical for protein synthesis and to ensure correct cell functioning. Mutations in the protein synthesis machinery or environmental factors that increase synthesis of mistranslated proteins result in cell death and degeneration and are associated with neurodegenerative diseases, cancer and with an increasing number of mitochondrial disorders. Remarkably, mRNA mistranslation plays critical roles in the evolution of the genetic code, can be beneficial under stress conditions in yeast and in Escherichia coli and is an important source of peptides for MHC class I complex in dendritic cells. Despite this, its biology has been overlooked over the years due to technical difficulties in its detection and quantification. In order to shed new light on the biological relevance of mistranslation we have generated codon misreading in Saccharomyces cerevisiae using drugs and tRNA engineering methodologies. Surprisingly, such mistranslation up-regulated the longevity gene PNC1. Similar results were also obtained in cells grown in the presence of amino acid analogues that promote protein misfolding. The overall data showed that PNC1 is a biomarker of mRNA mistranslation and protein misfolding and that PNC1-GFP fusions can be used to monitor these two important biological phenomena in vivo in an easy manner, thus opening new avenues to understand their biological relevance.

PNC1 is a longevity gene because its biochemical activity feeds into the sirtuin pathway: Pnc1p synthesizes nicotinic acid from nicotinamide, which is an inhibitor of Sir2p, one of the canonical longevity factors in S. cerevisiae. Overexpression of PNC1 increases lifespan, presumably by increasing the activity of Sir2p. (The authors show that Sir2p silencing activity is elevated under conditions that cause mistranslation, and that this is inhibited by exogenous nicotinamide. Missing, as far as I can tell, is the same experiment in ∆pnc1 cells, which according to the authors’ model would not induce silencing during mistranslation.)

Is this simply an example of a general stressor activating a general stress response, whose constitutive activation in turn makes cells more stress-resistant and therefore longer-lived? For example, one could imagine a translation fidelity problem resulting in synthesis of lots of poorly folded proteins, leading to activation of the heat shock response and expression of chaperones (indeed, in the worm, heat shock transcription factor HSF-1 is required for life extension by daf-2 mutations). This doesn’t appear to be that. Instead, loss of protein fidelity causes upregulation of a major longevity assurance pathway, which acts primarily at the level of transcriptional silencing.

A couple of questions:

• What is the relevant molecular correlate of translation infidelity? Unfolded proteins would be the most likely culprit (prediction: whether or not it’s involved in the lifespan extension, there should be some heat shock response under these conditions), but one can imagine more elaborate scenarios: Suppose an inhibitor of PNC1 translation is encoded by an mRNA that is particularly likely to be mistranslated under normal conditions (e.g., because of weird codon usage, secondary structure, or some other quirk) and is now translated so poorly that it loses its inhibitory activity altogether (or acquires a new activity).

• How is the translational upregulation of PNC1 mediated? This is particularly curious given that, by assumption, a cell with a high rate of translation infidelity is having difficulty with translation. Teleologically, there’s no reason not to regulate gene expression at this level — if the gene were upregulated transcriptionally, the mRNA would still have to be translated — but it still strikes me as odd. If this is a bona fide evolved response to translation problems, wouldn’t it be better to pre-synthesize PNC1 and then activate it post-translationally (e.g. by proteolysis)?

• Is SIR2 involved in translation fidelity? Looking at this story as a straightforward stress response, one would expect some action of SIR2 to help mitigate the stress that started the whole process. So I’d be curious to know whether SIR2 mutants have lower translation fidelity, and if so, how it is that SIR2 is involved in improving the accuracy of translation?

Silva, R., Duarte, I., Paredes, J., Lima-Costa, T., Perrot, M., Boucherie, H., Goodfellow, B., Gomes, A., Mateus, D., Moura, G., & Santos, M. (2009). The Yeast PNC1 Longevity Gene Is Up-Regulated by mRNA Mistranslation PLoS ONE, 4 (4) DOI: 10.1371/journal.pone.0005212

 

The free radical theory of aging: A retrospective by its creator

The free radical theory of aging (FRTA) was first advanced by Denham Harman more than 50 years ago. The theory proceeds logically from a small number of straightforward assumptions, based on observations from radiation biology. From the Science of Aging Timeline:

Harman’s logic proceeds from three observations: (1) irradiation causes premature aging; (2) irradiation creates oxygen radicals, which may mediate its effects; and (3) cells produce oxygen radicals under normal conditions. From these premises, he theorized that aging could be caused by endogenously generated oxygen radicals.

Over a half-century, the FRTA has evolved substantially (eventually focusing on the mitochondria as a major source of the initially postulated endogenous radicals), and has lately been the subject of several reviews evaluating its explanatory power and extent of current acceptance.

A unique perspective on the FRTA’s history has recently been provided by none other than its initiator, Denham Harman, who is retired but still intellectually active. From his review:

Origin and evolution of the free radical theory of aging: a brief personal history, 1954–2009

Aging is the progressive accumulation in an organism of diverse, deleterious changes with time that increase the chance of disease and death. The basic chemical process underlying aging was first advanced by the free radical theory of aging (FRTA) in 1954: the reaction of active free radicals, normally produced in the organisms, with cellular constituents initiates the changes associated with aging. The involvement of free radicals in aging is related to their key role in the origin and evolution of life. The initial low acceptance of the FRTA by the scientific community, its slow growth, manifested by meetings and occasional papers based on the theory, prompted this account of the intermittent growth of acceptance of the theory over the past nearly 55 years.

It’s a very personal account, starting with the educational experiences that Harman credits with putting him in the right place at the right time, continuing with a description of the origins of the theory, and paying a great deal of attention to the “fits-and-starts” advancement of the theory toward broad acceptance (though not without effort and extensive modification). Pieces like these, in which the originator of a hugely influential theory provides their individual perspective on the consequences of their work, are rare indeed — hence this is a must-read for students and practitioners of biogerontology.

Harman, D. (2009). Origin and evolution of the free radical theory of aging: a brief personal history, 1954–2009 Biogerontology DOI: 10.1007/s10522-009-9234-2

 

Am I hot or not? Thermosensory neurons regulate lifespan at high temperatures

Things happen faster when it’s warmer. This is true all the way down to the molecular level: many chemical reactions are accelerated at increased temperature. This leads to a fairly straightforward potential explanation for the longstanding observation that among organisms that are unable to regulate their own body temperature, higher temperature means a shorter lifespan — namely, the biochemical changes that underlie aging are simply happening faster.

This is probably true to some extent, but it’s not the whole story. A study by Lee and Kenyon reveals that there is active bioregulation of lifespan in response to temperature:

Background
Many ectotherms, including C. elegans, have shorter life spans at high temperature than at low temperature. High temperature is generally thought to increase the “rate of living” simply by increasing chemical reaction rates. In this study, we questioned this view and asked whether the temperature dependence of life span is subject to active regulation.

Results
We show that thermosensory neurons play a regulatory role in the temperature dependence of life span. Surprisingly, inhibiting the function of thermosensory neurons by mutation or laser ablation causes animals to have even shorter life spans at warm temperature. Thermosensory mutations shorten life span by decreasing expression of daf-9, a gene required for the synthesis of ligands that inhibit the DAF-12, a nuclear hormone receptor. The short life span of thermosensory mutants at warm temperature is completely suppressed by a daf-12(-) mutation.

Conclusions
Our data suggest that thermosensory neurons affect life span at warm temperature by changing the activity of a steroid-signaling pathway that affects longevity. We propose that this thermosensory system allows C. elegans to reduce the effect that warm temperature would otherwise have on processes that affect aging, something that warm-blooded animals do by controlling temperature itself.

In other words, higher temperatures do indeed shorten lifespan, but they shorten them even more if the animal is unaware of the higher temperatures. Thermosensory neurons sense the adverse conditions and presumably activate a program that counteracts the life-shortening effects of a warmer environment.

Despite the rhetoric in the abstract, this doesn’t put an end to the “rate of living” hypothesis. There’s clearly a shortening of lifespan in response to elevated temperature; the existence of a pathway that limits that shortening doesn’t argue either way about the role (if any) played by the acceleration of biochemical reactions or cellular/systemic events at under warmer conditions.

So, then: what’s the mechanism of the relative lifespan extension conferred by thermosensory neurons? Still unknown, but given the well-funded lab group in question, I’d be surprised if an expression profiling experiment were far behind. My money is on heat shock proteins, regulated not in response to heat, but in response to neuroendocrine factors secreted by temperature-sensitive nerve cells.

Lee, S., & Kenyon, C. (2009). Regulation of the Longevity Response to Temperature by Thermosensory Neurons in Caenorhabditis elegans Current Biology DOI: 10.1016/j.cub.2009.03.041