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

 

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

 

Reviewing the reviews (#4, in case you’re counting)

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:

• Regulation of the aging process by autophagy, Salminen & Kaarniranta

Chaperones:

• Hsps and aging, John Tower (who is capable of giving reviews more colorful titles)

Evolution:

• The Evolutionary Theories of Aging Revisited – A Mini-Review, Ljubuncic & Reznick

Glycation:

• The receptor for advanced glycation endproducts (RAGE) and cardiovascular disease, Yan et al.

Immunology:

• The Role of Stress Factors during Aging of the Immune System, Bauer et al.
• Key Research Opportunities in Immune System Aging, Swain & Nikolich-Zugich

Mitochondria:

• Functions of mitochondria: from intracellular power stations to mediators of a senescence program, V. P. Skulachev

Neurodegeneration:

• A metabolic and functional overview of brain aging linked to neurological disorders, Baquer et al.

Resveratrol:

• Resveratrol and chemoprevention, Goswami & Das

Senescence:

• Cellular senescence, ageing and disease, D. G. A. Burton

 

Reviewing the reviews

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:

• Relationships between cancer and aging: a multilevel approach, Anisimov et al.

Endocrinology:

• Metabolic Journey to Healthy Longevity, Barbieri et al.

IGF-1:

• Insulin/IGF-like signalling, the central nervous system and aging, Broughton & Partridge

Inflammation:

• Atypical pathways of NF-κB activation and aging, Kriete & Mayo

Mitochondria:

• The mitochondrial theory of aging: Insight from transgenic and knockout mouse models, Jang & Van Remmen

Sarcopenia:

• Proteomics of skeletal muscle aging, Doran et al.

Stem cells:

• Stem Cells Use Distinct Self-renewal Programs at Different Ages, Levi & Morrison

Telomeres:

• Telomeres and reproductive aging, Keefe & Liu

 

SIRT6 follows in SIRT1′s footsteps

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.)

 

Timing of CR diet initiation affects immune senescence

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.

 

The secondary literature, or, how I learned to stop worrying and love the review

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:

• How to Live Long and Prosper: Autophagy, Mitochondria, and Aging, Yen & Klionsky

CR & IGF-I:

• Longevity Genes: Insights from Calorie Restriction and Genetic Longevity Models, Shimokawa et al.

DNA damage & gene expression:

• DNA damage and ageing: new-age ideas for an age-old problem, Garinis et al. (this is an absolute must-read if, like so many others, your head exploded when you first grappled with this story or its predecessors)

Immunology:

• Inflammation: Roles in Aging and Sarcopenia, Jensen

Insulin:

• The insulin paradox: aging, proteotoxicity and neurodegeneration, Cohen & Dillin
• Insulin and aging, Bartke

Progeria:

• Model of human aging: recent findings on Werner’s and Hutchinson-Gilford progeria syndromes, Ding & Shen

Stochasticity:

• Nature, Nurture, or Chance: Stochastic Gene Expression and Its Consequences, Raj & van Oudenaarden (this isn’t a particularly aging-focused review but it places observations like these and these within a larger context in systems biology)

TOR signaling:

• Aging: ROS or TOR, Blagosklonny (who has argued that the TOR inhibitor rapamycin might be a useful anti-aging therapeutic)

Yeast:

• A mother’s sacrifice: what is she keeping for herself?, Henderson & Gottschling (a very thought-provoking discussion of the ramifications of asymmetric cell division in aging, and the search for yeast “senescence factors”; this entire issue was basically ignored — by me — in a recent wide-ranging discussion of recent progress in yeast aging studies)

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.

 

SIRT1 in metabolism, signaling and disease

Racing toward its ultimate goal of being involved in every aspect of biology, the mammalian sirtuin SIRT1 has been the subject of a number of recent papers, each dealing with a different aspect of the protein’s role. (Abstracts are excerpted; ellipses, emphases, and interpolated commentary are mine.)

In energy metabolism and liver cirrhosis: Sirt1 is involved in energy metabolism: The role of chronic ethanol feeding and resveratrol, Oliva et al.:

These results support the concept that ethanol induces the Sirt1/PGC1α pathway of gene regulation and both naringin and resveratrol prevent the activation of this pathway by ethanol. However, resveratrol did not reduce the liver pathology caused by chronic ethanol feeding [In other words, it's probably not a good idea to get your resveratrol by drinking 1000 bottles of red wine a day.]

In diseases of protein aggregation: The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration, Chen et al. [a collaboration between the Lindquist and Guarente labs]:

We tested the role of SIRT1 in mediating the effects of CR in a mouse model of prion disease. … We report that the onset of prion disease is delayed by CR and in the SIRT1 KO mice fed ad libitum. CR exerts no further effect on the SIRT1 KO strain, suggesting the effects of CR and SIRT1 deletion are mechanistically coupled. In conjunction, SIRT1 is downregulated in certain brain regions of CR mice. … Surprisingly, CR greatly shortens the duration of clinical symptoms of prion disease and ultimately shortens lifespan of prion-inoculated mice in a manner that is independent of SIRT1. [i.e., CR isn't actually therapeutically beneficial since the mice die young.]

In inflammation, inflammaging, and HIV/AIDS: SIRT1 longevity factor suppresses NFκB -driven immune responses: regulation of aging via NFκB acetylation?, Salminen et al. (review):

HIV-1 Tat protein binds to SIRT1 protein, a well-known longevity factor, and inhibits the SIRT1-mediated deacetylation of the p65 component of the NFκB complex. As a consequence, the transactivation efficiency of the NFκB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. … Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NFκB signaling, the major outcome of which is inflamm-aging via proinflammatory responses.

In Notch regulation of stem cell aging: Sirt1, Notch and stem cell “age asymmetry”, Mantel et al. (review):

The protein-deacetylase, SIRT1, has received much attention because of its roles in oxygen metabolism, cellular stress response, aging, and has been investigated in various species and cell types including embryonic stem cells. However, there is a dearth of information on SIRT1 in adult stem cells, which have a pivotal role in adult aging processes. Here, we discuss the potential relationships between SIRT1 and the surface receptor protein, Notch, with stem cell self-renewal, asymmetric cell division, signaling, and stem cell aging.

 

Inflammation, aging, and cancer

A number of relatively recent review articles have discussed the connections between inflammation and aging, as well as between aging and cancer. The connections between all three of these scourges have now been reviewed by Vasto et al., who pay special attention to the neglected arm of the triangle — the relationship between inflammation and tumorigenesis.

Inflammation, ageing and cancer

Cancer is generally recognized as an age-related disease. In fact, incidence and mortality rates of most human cancers increase consistently with age up to 90 years, but they plateau and decline thereafter. A low-grade systemic inflammation characterizes ageing and this pro-inflammatory status underlies biological mechanisms responsible for age-related inflammatory diseases. On the other hand, clinical and epidemiological studies show a strong association between chronic infection, inflammation and cancer and indicate that even in tumours not directly linked to pathogens, the microenvironment is characterized by the presence of a smouldering inflammation, fuelled primarily by stromal leukocytes. In this review, we have briefly mentioned inflammatory mediators involved in cancer although we decided to choose the ones which show a strict association with ageing and longevity. Inflammation is necessary to manage with damaging agents and is crucial for survival. But, in our opinion, the pro-inflammatory status of ageing might be one of the mechanisms which relate cancer to ageing. The most appropriate inflammatory genes have been selected to survive and to reproduce. Paradoxically, inflammatory age-related diseases (including cancer) are the marks of the same evolutionistic trait. Centenarians are characterized by a higher frequency of genetic markers associated with better control of inflammation. The reduced capacity of centenarians to mount inflammatory responses appears to exert a protective effect towards the development of those age-related pathologies having a strong inflammatory pathogenetic component, including cancer. All in all, centenarians seem to carry a genetic background with a peculiar resistance to cancer which is also an anti-inflammatory profile.

Note that bit about centenarians at the end of the abstract. The reduction in inflammatory capacity they’re talking about isn’t large (not even two-fold at the level of primary cytokine output, though quantifying the difference depends ultimately on which endpoint one is measuring), so the observation gives credence to the idea that tailored anti-inflammatory drugs — perhaps targeted to individual tissues, or to specific types of cytokine responses — might help slow aging in tissues throughout the body.

In the meantime, keep popping those baby aspirins.

 

Keeping up with IGF-I and FOXO

Ever since the discovery that loss-of-function daf-2 mutations extend lifespan in C. elegans (a phenotype for which the forkhead-like transcription factor daf-16 is required), biogerontologists have devoted a tremendous amount of attention to the pathway, both in worm and in mammal (where DAF-2 and DAF-16 have homologs: insulin-like growth factor receptor (IGF-I-R) and various FOXO proteins, respectively).

As I mentioned yesterday, this week I’m clearing the backlog of articles that has accumulated over the past couple of months. Lots has been happening on the IGF/FOXO front. As always, each of these papers probably deserves its own post, but time is not permitting. Quoted passages are excerpts from the abstracts.

Low IGF-I decreases cancer: Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Low Circulating Insulin-Like Growth Factor I Levels, Moore et al.:

These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.

Downregulating IGF-I enhances stress tolerance: Cellular conditioning with trichostatin A enhances the anti-stress response through up-regulation of HDAC4 and down-regulation of the IGF/Akt pathway, Chu et al.:

Interestingly, the insulin signaling pathway mediated by Akt was inhibited in the TSA-resistant cells, mirroring the effect of glucose deprivation on this pathway. … Together, these findings suggest that cellular conditioning with TSA may represent a useful approach to mimic the effects of caloric restriction.

Inflammation: Regulation of IGF-I function by proinflammatory cytokines: At the interface of immunology and endocrinology, O’Connor et al.:

Over the past decade, research in our laboratory has focused on the ability of the major proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-1β, to induce a state of IGF resistance. This review will highlight these and other new findings by explaining how proinflammatory cytokines induce resistance to the major growth factor, insulin-like growth factor-I (IGF-I).

Gonadal regulation: Drosophila germ-line modulation of insulin signaling and lifespan, Flatt et al.:

Here we report that eliminating germ cells (GCs) in Drosophila melanogaster increases lifespan and modulates insulin signaling. … These results suggest that signals from the gonad regulate lifespan and modulate insulin sensitivity in the fly and that the gonadal regulation of aging is evolutionarily conserved.

Target genes: Identification of Direct Target Genes Using Joint Sequence and Expression Likelihood with Application to DAF-16, Yu et al.:

We found that 189 genes were tightly regulated by DAF-16. In addition, DAF-16 has differential preference for motifs when acting as an activator or repressor, which awaits experimental verification.

Stem cells: FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic System, Tothova and Gilliland:

… FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems.

As therapeutic targets: OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins, Malese et al.:

Forkhead transcription factors have a ‘winged helix’ domain and regulate processes that range from cell longevity to cell death. … Here we discuss recent advances that have elucidated the unique cellular pathways and clinical potential of targeting FoxO proteins to develop novel therapeutic strategies and avert potential pitfalls that might be closely intertwined with its benefits for patient care.

There’s plenty to chew on. Tomorrow: telomeres.