Immunology


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.

Gene regulation:

Inflammation:

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.

Nuclear organization:

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.

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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.

ResearchBlogging.orgMitteldorf, 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

Here’s the latest in our (infrequent and irregular) series of “review roundups” — links, without extensive further comment, to the reviews I found most intriguing over the past few weeks. For the previous foray into the secondary literature, see here.

Remember, each Review Roundup is guaranteed to contain at least one link to a review you will find highly educational, or your money back.

Autophagy:

Chaperones:

Evolution:

Glycation:

Immunology:

Mitochondria:

Neurodegeneration:

Resveratrol:

Senescence:

Here’s the latest in our series of review roundups — links, without extensive further comment, to the reviews I found most intriguing over the past few weeks. For the previous foray into the secondary literature, see here.

Cancer:

Endocrinology:

IGF-1:

Inflammation:

Mitochondria:

Sarcopenia:

Stem cells:

Telomeres:

Sirtuins are involved in longevity assurance in organisms as evolutionarily diverse as yeast, worms, and mice. All members of the family have homology to histone deacetylases (HDACs), but each protein has unique characteristics as well. Individual family members have distinct tissue expression profiles, subcellular localization, and substrate specificity. Over the past few years, we’ve begun to learn a great deal about the specific targets and interactions of each sirtuin, and how these interaction contribute to their functions in prolonging lifespan.

The SIRT6 protein, one of seven sirtuins encoded by mammalian genomes, came onto biogerontologists’ radar with a report from Katrin Chua‘s group that its histone H3K9 deacetylase activity is required to maintain telomeric chromatin in a healthy state. Furthermore, SIRT6 is required for the proper localization of the Werner’s syndrome protein, WRN, to telomeres: in the absence of SIRT6, the WRN-telomere association becomes unstable, recapitulating several of the cellular phenotypes of Werner’s progeria. (SIRT6 isn’t the only sirtuin involved in WRN biology: SIRT1, the most well-studied member of the family, appears to directly deacetylate WRN).

A second association between SIRT6 and aging has been revealed by a new study from the Chua lab: SIRT6 associates with the transcription factor NF-κB and deacetylates histones at NF-κB-bound promoters, causing them to become less active. Genetic suppression studies suggest that SIRT6’s influence on lifespan might be primarily mediated by NF-κB. Kawahara et al.:

SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF-κB-Dependent Gene Expression and Organismal Life Span

Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-κB signaling. SIRT6 interacts with the NF-κB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-κB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-κB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-κB-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-κB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-κB signaling may contribute to premature and normal aging.

NF-κB has been widely implicated in the aging process, especially in the context of inflammatory transcription resulting in “inflammaging.” Indeed, a very recent study has suggested that knocking down NF-κB activity is sufficient to reverse the effects of chronological aging in the skin, at least at the level of gene expression, possibly by blocking inflammatory transcription and allowing the tissue’s natural regenerative capacity to proceed without obstacle.

As with the WRN story, this isn’t the first time a sirtuin has been implicated in regulating the activity of NF-κB — but also as with WRN, the mechanisms of sirtuin action are distinct. Studies of chronic obstructive pulmonary disease have revealed that SIRT1 directly deacetylates NF-κB, reducing its activity. In contrast, SIRT6 appears to associated with NF-κB but then exploit this interaction to “follow” the transcription factor to promoters, where it deacetylates histone H3K9 and facilitates formation of a closed or inactive chromatin state. Kind of a neat team: SIRT1 directly deacetylates proteins of interest, while SIRT6 acts in the same location but operates on chromatin. Working together, the proteins may well have greater than additive impact.

Thus, there is partial redundancy of ultimate function, even though the proteins operate via different mechanisms. This might actually make it easier to intervene favorably in the affected processes, if separate agonists of SIRT1 and SIRT6 end up having a synergistic effect at target promoters (and telomeres).

(There’s also a nice preview/summary piece in the same issue of Cell, by Gioacchino Natoli.)

Immune senescence, or a reduction in immune responses, occurs along with many other organ system declines observed in human aging. Immune senescence is characterized by a reduction of naïve T and B lymphocytes and an increase in T and B memory cells. This population shift of lymphocytes causes a reduced response to infection and vaccination as well as an increase in inflammatory cytokines that can contribute to many age-related diseases.

Calorie restriction (CR) diets have been shown to increase the health and lifespan of many model animals. Specifically, in short lived rodent models, these beneficial effects have improved immune system function by enhancing immune competence, inhibiting age-related dysregulation of cytokine secretion, and by preventing the accumulation of senescent T cells through increasing apoptosis.

In a paper previously published by Messaoudi et al. the researchers found that CR diets in long-lived Rhesus monkeys (RM) increased the number and function of naïve and memory T-cells, thus delaying the immune senescence seen in aging immune systems and reproducing the results seen in short-lived model organisms.

In their most recently published study, Messaoudi et al. analyzed the effect of the age-of-onset of CR diets on T-cell homeostasis and function in RM to ascertain the importance of timing the initiation of CR diets throughout the lifespan of RM. In this study, RM began a CR diet as juveniles or in advanced age. In both cases, a CR diet started before or after adulthood negatively impacted immune function.

Optimal window of caloric restriction onset limits its beneficial impact on T-cell senescence in primates.

We have recently shown in non-human primates that caloric restriction (CR) initiated during adulthood can delay T-cell aging and preserve naïve CD8 and CD4 T cells into advanced age. An important question is whether CR can be initiated at any time in life, and whether age at the time of onset would modulate the beneficial effects of CR. In the current study, we evaluated the impact of CR started before puberty or during advanced age on T-cell senescence and compared it to the effects of CR started in early adulthood. Our data demonstrate that the beneficial effects of adult-onset CR on T-cell aging were lost by both early and late CR onset. In fact, some of our results suggest that inappropriate initiation of CR may be harmful to the maintenance of T-cell function. This suggests that there may be an optimal window during adulthood where CR can delay immune senescence and improve correlates of immunity in primates.

The peripheral blood of the juvenile CR cohort had the same number of circulating lymphocytes but there was a significant decrease in naïve T cells, and a significant increase in memory T-cells. Additionally, the researchers noted in addition to the decrease in T-cell diversity, an increase in T-cells secreting pro-inflammatory cytokines, and a loss of proliferative potential of T-cells suggesting that early onset of CR diets negatively impacts T-cell aging in male RM.

These phenotypes were not seen in the female juvenile CR cohort. The authors state that this could be due to the fact that the females were 5 years younger on average than the males at the time of peripheral blood sampling. Alternatively, the authors suggest that there may be sex specific effects of CR diets in these animals. But since they did not observe any sex specific differences in their previous study of adolescent CR, the authors conclude that it is more likely that sex differences observed are due to the age discrepancy at the time of the data collection. It will be informative to assess these females in another 5 years to determine if their phenotype mimics the phenotype observed in the males presented here.

In the old age CR cohort, there was no decrease in the population diversity in the circulating T-cells and no difference in numbers of T-cells secreting pro-inflammatory cytokines. However there was an overall reduction in white blood cells, specifically neutrophils, but it is unclear if this phenotype has a detrimental or beneficial effect. Old age CR also resulted in a decreased proliferation potential in T-cells indicating a negative impact of advanced age CR on RM.

This study highlights that appropriate timing of calorie restriction diet onset is critical to observing the beneficial effects on immune senescence. These data also reveal the importance of proper caloric intake during development for healthy immune function. As we improve our understanding of the specific molecular mechanisms by which CR improves health and lifespan we will be better able to treat age-related diseases. Additionally, these non-human primate studies will be exciting to follow as they may prove to be the most relevant animal model to enhance our understanding of molecular mechanisms behind CR diets in humans.

Sometimes I feel like our field produces review articles faster than it produces good ideas. Certainly, biogerontology generates more reviews in a given week than truly significant papers, but the same might be said of any discipline.

I’ve been ambivalent about how to deal with reviews — I’ve considered ignoring them altogether, only covering the “important ones,” link-dumping a bunch of them whenever I was too lazy to write a real post, and various other hybrid strategies. Ignoring them seemed most attractive, since our main mission at Ouroboros is to review the primary literature, so reviewing reviews seemed pointless and derivative.

But a recent reader inquiry (from one of our junior colleagues who basically wanted me to do some of their homework for them; my response was basically “read a review and make up your own mind”) reminded me of the importance of review articles: They’re a great way for scientists who aren’t already expert in a field to figure out where the important questions are. The best ones also juxtapose the most current efforts in creative and interesting ways, adding value by pointing out non-obvious connections between subfields. If read closely and attentively, reviews can be the source of great inspiration.

So rather than treating the elements of the secondary literature like second-class citizens, I’m going to start a quasi-regular feature wherein I (or one of the other writers) compile a list of the most important and interesting reviews of the last couple of weeks, and link to them without much further comment (thereby avoiding the vaguely ridiculous feeling of reviewing reviews, which would make one — what? — the “tertiary literature”?). You, the reader, can do what you wish with them. This new feature of Ouroboros begins…NOW!

Autophagy:

CR & IGF-I:

DNA damage & gene expression:

Immunology:

Insulin:

Progeria:

Stochasticity:

TOR signaling:

Yeast:

Like I said, I’ll do something like this every couple of weeks, or whenever the review folder gets full. That way we’ll never fall too far behind.

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