Mitochondria play central rols in the aging process. The macromolecular damage that occurs over the course of aging, including both frank mitochondrial mutation and insults elsewhere in the cell, impairs mitochondrial function. This, in turn, decreases the amount of energy the cell can generate by oxidative phosphorylation (ox-phos), and this steady deterioration of energy production is thought to underlie many diseases associated with aging.

The brain is particularly vulnerable to aging (q.v. the plethora of age-associated neurodegenerative disorders) and mitochondrial defects in particular. It’s not hard to imagine why: neurons and other brain cells are energy-intensive, accounting for some twenty percent of the body’s calorie burn, so we would expect attenuation of ox-phos to hit them particularly hard.

In terms of aging more generally, neurons are highly specialized cells with limited self-renewal capacity, and they are unable to avail themselves of certain kinds of cellular garbage disposal—for example, they can’t grow to dilute out detritus. Consequently, if their recycling pathways fall behind the rate at which the cell produces unwanted components (including, importantly in this regard, defective mitochondria), the trash will start to build up, further compromising function.

To better understand these phenomena, we would like to have a tractable cell-culture system in which to study neuronal aging. However, this is easier said than done: As we just noted, neurons don’t divide, so the researcher is more or less stuck with the first cells to hit the Petri dish. In any case, more people object to having their neurons removed from their skulls, even if it is for a good cause.

(Yes, I hear the squeaking in the back: we could use cultures [or slices or explants] of mouse neurons. However, as noted here recently, mice are imperfect models of human brain aging: for example, without massive genetic manipulation, they do not develop age-related dementia. Accordingly, it would be preferable to use human neurons, bringing us back to the objection raised in the previous paragraph, before I launched into this digressive but hopefully instructive parenthetical.)

Happily, we have ways of making neurons in vitro, starting not with brain tissue but with cells that most humans are far more willing to part with. For example, the humble fibroblast, a cell type present in almost every tissue (except, notably, the brain), can be induced to de-differentiate by the introduction of a surprisingly small number of factors (thank you, Shin Yamanaka). The resultant ‘induced pluripotent stem cells’ (iPSCs) can then be (re-)differentiated into a variety of cell types, including neurons.

Great news, right? Well, almost: inconveniently for our purposes, iPSCs “forget” most aspects of their former cellular state, including mitochondrial phenotypes and other markers of chronological age, making neurons derived from them unsuitable for studies of age-related change.

Fortunately, however, fibroblasts can be directly reprogrammed without having to pass through the tabula rasa state of iPSCs. The resultant ‘induced neurons’ (iNs) preserve information about aging, including age-associated transcriptional signatures and nucleocytoplasmic defects.

OK, back to mitochondria. One of the groups that pioneered the production and use of iNs has published a new study focusing on the mitochondrial phenotypes of these cells, specifically as they relate to aging.

The found that iNs created from fibroblasts from old donors had significant impairment in ox-phos, largely due to downregulation of the genes encoding components of the electron transport chain. Consequently, these cells were considerably less competent to produce energy, and they exhibited morphological hallmarks of age-associated neurodegeneration.

The authors argue that their findings support a bioenergetic explanation for neurons’ vulnerability to the ravages of aging. In other words, the metabolic shift that accompanied the conversion from fibroblasts to neurons causes the cells to be more dependent on ox-phos and therefore more susceptible to mitochondrial dysfunction.

Ultimately, these features make iNs from elderly donors a powerful tool for studying age-related decline in neuronal function, as well as the pathogenesis of neurodegenerative disease. A readily available source of cells that faithfully recapitulate the mitochondrial deterioration associated with normal human aging could enable high-throughput screens for drug leads that slow or even reverse these deleterious changes.

Somewhat more speculative, but still intriguing, is the idea that by comparing neurons derived from iPSCs (which “forget” the chronological age of the original cells, including mitochondrial defects) with iNs (which “remember”), we could obtain insight into the cellular tricks by which some cells can rejuvenate their own mitochondria, and thereby themselves.

Kim et al. “Mitochondrial Aging Defects Emerge in Directly Reprogrammed Human Neurons due to Their Metabolic Profile.” Cell Reports 23(9): 2550–2558 (2018) DOI: 10.1016/j.celrep.2018.04.105

As noted here recently, model organisms are essential to biogerontology: given the evolutionary conservation of aging-related pathways, we should be able to learn about human aging by studying animals with shorter lifespan. Models can be assessed in a variety of ways, often in terms of ease of use (e.g., being genetically tractable or having a short lifespan) or how closely they resemble humans (e.g., in terms of genetic relatedness or similarity of life history).

Unfortunately, there tends to be a tradeoff between those two features: the easiest animals to work with in the laboratory are the most different from humans. Miceare unquestionably important models: their 2–3-year lifespan makes them ideal for longevity studies, and they are very similar to humans in particular biochemical and cell-biological ways. However, the spectrum of age-related disease in mouse differs from that of humans (among other things, wild-type mice don’t really develop cardiovascular disease or dementia), and the environments in which they live differ as well.

This raises serious challenges to the model organism dogma that if an anti-aging intervention works in mice, it will probably work in humans: Aging pathways are conserved between the two species, but specific aspects of the aging process differ dramatically.

As an alternative, some have proposed the companion dog, a model that would sacrifice some ease of use in exchange for a closer approximation of human aging. Dogs are indeed longer-lived than rodents, with lifespans just under an order of magnitude longer than those of mice, and a similar amount shorter than ours. Furthermore, they share our environment, literally living in our homes with us and (whether or not they’re supposed to) eating the same food.

But is the aging process in dogs really similar to that in humans? A recent study answers in the affirmative, providing key support for the idea that dogs could be used to understand normal aging in humans and test anti-aging medicines.

The authors used data from more than 100,000 people and nearly as many dogs in the US and UK to compare the patterns of age-related mortality and morbidity (here meaning “the rate of disease”) between the two species. They found extensive similarities: the survival curves are very similar (when normalized against maximum lifespan), as is the incidence of chronic conditions arising with advanced age. The rank order of causes of death are also strongly correlated (subject to a qualification that we’ll address below), the proportion of individuals dying of cancer at each normalized age is comparable, and—when we exclude lifestyle-related diseases (e.g., lung cancer caused by smoking) —the same organ systems are involved. 

The major difference between dogs and humans is that we get far more cardiovascular diseases than our best friends, which is somewhat surprising given that we think of CVD as a lifestyle-related disease, and dogs and humans share both environmental influences and to some extent lifestyle (e.g., fun fact: obese people are likelier to have obese dogs). The authors argue that this is still informative, as it implies that the difference in CVD incidence is genetically determined, allowing us to learn about CVD pathogenesis in humans by investigating the differences between the cardiovascular systems of canines and primates.

Nonetheless, the similarities are striking, providing important evidence that dogs could serve as both a fundamental model (i.e., to learn about the molecular details of aging) and a translational model (i.e., to test interventions on a shorter timeframe than would be possible in humans). Some of this work is already underway, and I direct interested readers to the Dog Aging Project for the details of longitudinal lifespan studies and even an intervention study involving rapamycin. (The DAP is one of my favorite things in biogerontology, but rather than shortchange it by trying to summarize here, I’ll devote a full post or two to the project at a later time.)

The benefits of helping dogs live longer are manifold—not only will it help us test medications that could someday be used to extend healthspan in humans, it will enable us to keep our beloved companions around for longer, enriching our own lives in the countless ways that they do. As anyone who has ever loved a dog knows, this is an end in itself.

Hoffman et al. “The companion dog as a model for human aging and mortality.” Aging Cell 19 Feb 2018. DOI:10.1111/acel.12737

If only because of the size of the heap, I nonetheless still suspect that there’s a pony in there somewhere; I’ve often wished I had the time to do a comprehensive literature review of my own, so that I could identify the compounds whose associated claims are supported by the best evidence. Now it looks like I can start wishing for something else, because someone did it for me.

At the (amazing) blog Information is Beautiful, David McCandless and Andy Perkins have assembled a “generative data-visualisation of all the scientific evidence for popular health supplements“. In David’s words:

I’m a bit of a health nut. Keeping fit. Streamlining my diet. I plan to live to the age of 150 in fact. But I get frustrated by constant, conflicting reports and studies about health supplements.

Is Vitamin C worth taking or not? Does Echinacea kill colds? Am I missing out not drinking litres of Goji juice, wheatgrass extract and flaxseed oil every day?

In an effort to give myself a quick reference guide, I dove into the scientific evidence and created a visualization for my book. And then worked with the awesome Andy Perkins on a further interactive, generative “living image”.

The image itself is dynamic with respect to both user input about what information is desired, and introduction of new data – it is based on the information in a spreadsheet, which can be updated (new compounds, or information about compounds already mentioned), altering the visual rendering the dynamic image. You can play with the image here; I’ve attached a still snapshot below.

The rendering is imperfect (as also discussed elsewhere): More reliable claims are near the top, and more dubious claims are near the bottom, but this positioning is the result of a single variable, “evidence,” which may the based largely on a citation count. This is a problem because not all citations that mention a compound should be weighted equally; furthermore, it’s not clear how conflicting claims end up getting counted. The abstraction of a complex body of data into a single number unquestionably involves some judgment calls that could be made differently – that’s not necessarily a lethal criticism, but the process should be as transparent as possible.

On a visual level, the image is attractive, but color is mostly a wasted variable: position along the color spectrum is synonymous with height — except in the case of orange, which indicates a compound with “low evidence, promising results”. The orange compounds are still assigned an evidentiary weight, according to an algorithm I can’t fathom; this is particularly confusing at both ends: beta-glucan is in the “high evidence” position, which seems to contradict the label’s definition (“low evidence”); whereas noni and astragalus are in the “no evidence” position, raising questions about how there could be “promising results”.

The strength of the project, however, is that it can evolve; the creators are already enthusiastically updating it. So far the changes (as detailed in this log) are content-oriented; one hopes that the methodology of generative data visualization will also enjoy improvements as time goes by.

Each approach can be further subdivided in terms of degree (85% of ad libitum calories, or 70%?), timing (alternate-day fasting or 5:2?), and duration (just for a month, or for life?). Each variant is likely to have a different efficacy in terms of health improvement and extension of the healthspan. An important aspect of efficacy is compliance: a regimen that is effective only if the subject is closely supervised is unlikely to be useful in the population at large.

Finally, the source of the benefits of CR and IF remains in question. For example, IF has been shown to improve various aspects of cardiometabolic health, but it remains unclear whether those were simply due to weight reduction—in which case we’re simply left with the age-old question of how best to encourage humans to lose weight.

A recent study has shed light on these issues. Sutton et al. report that that early time-restricted feeding (eTRF), in which the subject eats a normal amount of calories during a specific time interval early in the day, confers health improvements in human beings. Notably in regard to the questions raised above, the benefits were not dependent upon weight loss.

The benefits were diverse but not entirely comprehensive: eTRF improved certain aspects of cardiac health, such as blood pressure, but had no effect on cardiac stiffness or blood lipoprotein levels. Similarly, some markers of aging were downregulated (specifically, those related to oxidative stress), whereas inflammatory signals were unchanged. (Given that the regimen did not result in significant weight loss, this is not surprising: overall inflammatory tone is largely driven by factors produced by abdominal fat. No loss of fat,  no decrease in inflammation.)

The “e” in “eTRF” is important: the body’s hormone profile changes with the circadian rhythms; we are more insulin-sensitive in the morning than in the evening. Consistent with this, TRF is effective in rodent models only when feeding occurs in the early part of the waking day. (Pardon the elliptical construction; I deliberately avoided  saying “morning” in the previous sentence because rodents are, as we know, nocturnal).

Importantly, the eTRF regimen decreased the participants’ appetite later in the day, thus reducing the temptation to cheat. This has major implications for compliance: Humans eat when we shouldn’t for a lot of reasons, but mostly because some signal is telling us that we’re hungry. Eating a full daily complement of calories early in the day seems to attenuate the relevant hunger pathways, likely making it easier for subjects to stay with the program. (Although the authors don’t mention this, I would speculate that allowing the subject to live the same way every day, rather than eating on some days and not on others, would also make compliance easier.)

Indeed, the subjects reported that they found it more challenging to eat a day’s worth of food in 6 hours than to avoid food for 18 — in other words, it was easier to fast than to feast. Therefore, one wonders whether adopting eTRF might also induce some degree of CR, simply because the subjects aren’t hungry enough to eat even when they’re allowed to.

Sutton et al. “Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes.” Cell Metabolism (2018). DOI: 10.1016/j.cmet.2018.04.010

Boston-area biogerontologists take note: Registration is open for the annual Harvard Symposium on Aging, held at the Paul F. Glenn Center for the Biology of Aging at HMS. The event seeks to educate the wider research community about advancements in the fast-paced field of aging research and to stimulate collaborative research in this area.

Attendance is open to all members of the research community, and registration is free. Details are here.
.

Autophagy is particularly important in non-dividing cells such as neurons, which can’t simply dilute out cellular detritus by growing faster than the trash builds up. Accordingly, defects in autophagy are linked to age-related neurodegenerative diseases such as Alzheimer’s and ALS. Conversely, we are increasingly finding that enhancing autophagy can help to prevent such diseases, as well as mitigating age-related deterioration more generally.

Consistent with this paradigm, new work from Louis Lapierre‘s lab at Brown University shows that stimulating autophagy can increase lifespan in model organisms and even protect against neurodegeneration in a fly model. While this is not the first indication that boosting autophagy slows aging, the authors of this paper use a clever new way to achieve this end: they increased the nuclear accumulation of TFEB, a transcription factor responsible for expression of autophagic factors, by blocking its export from the nucleus.

In initial experiments, the authors interfered with export function through a genetic manipulation, but they subsequently showed that pharmacological inhibition of export using compounds known as SINEs (selective inhibitors of nuclear export) had the same effect: reduced nuclear export led to higher levels of TFEB in the nucleus, which in turn increased transcription of autophagy proteins and boosted the activity of the pathway.

They went on to show that SINEs could boost autophagic activity in a fly model of ALS, as well as in cultured human cells. The fact that the drug works in multiple, evolutionary distant organisms indicates that the targeted mechanism is conserved (i.e., rather than an idiosyncratic feature of a single species). Furthermore, in the ALS flies, the intervention significantly ameliorated neurodegeneration, implying that this approach could in principle be applied to treating some of the most devastating diseases associated with aging.

Also important from the standpoint of translational medicine is the identification of what the senior author called “a new and conserved entry point” into an important pro-longevity pathway. Autophagy is under the control of the TOR pathway, and inhibition of TOR both activates autophagy (in part by promoting nuclear localization of TFEB) and extends lifespan. However, as we discussed here recently, chronic inhibition of TOR runs the risk of deleterious side effects, and it would be ideal to target the relevant downstream effectors of TOR inhibition (i.e.,  the factors that are directly responsible for extension of longevity) without knocking down the entire pathway for an appreciable fraction of the adult lifespan.

SINEs fit the bill: they activate autophagy and extend lifespan, but (as the authors show) they leave the activity of the TOR pathway untouched. Notably in this regard, SINEs are already being tested as anti-cancer drugs, and previous work has demonstrated their preclinical efficacy as well as their safety and tolerability in human subjects. Assuming that these early results hold, SINEs represent promising candidates for treating or even preventing neurodegeneration and other age-related diseases by activating autophagy.

Silvestrini et al. “Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan.” Cell Reports, Volume 23 , Issue 7, pp.  1915 – 1921 (2018). DOI: 10.1016/j.celrep.2018.04.063

SaveSave

Have you ever wanted to direct the agenda for aging research on a national scale—even influence the overall shape of the field? Well, now’s your chance: the NIH is asking for your help in setting priorities for the third Geroscience Summit.

As attentive readers will have inferred, there have been two previous Geroscience Summits. The first, entitled “Advances in Geroscience: Impact on Healthspan and Chronic Disease,” was held in 2013, sought to establish a framework for collaborative and interdisciplinary research aimed at understanding how aging contributes to chronic disease. Three years later, the second summit (“Disease Drivers of Aging: 2016 Advances in Geroscience“) took the opposite approach, focusing on understanding how chronic diseases influence the rate of aging.

Both of these summits emerged from the GeroScience Interest Group (GSIG), an coalition spanning 21 of the 27 institutes and centers of the NIH (i.e., not limited to the NIA). The GSIG’s main missiong is to promote research on the common mechanisms underlying chronic diseases associated with aging, as well as identify cross-disciplinary opportunities to improve the health of elderly people.

The third summit has the ambitious goal of expanding the umbrella of geroscience. In their words:

This time, our goal will be to engage professional societies, stakeholder groups, and researchers interested in specific chronic diseases and conditions of older people, and exchange ideas on the role of aging biology in these health problems.

How that is accomplished, however, remains to be determined—and that’s where we come in. The NIA has posted a request for information (RFI) seeking input from non-governmental stakeholder organizations—including researchers, disease and aging patient advocacy groups, professional societies, the broader scientific research community, and the general public (i.e., pretty much everyone) regarding:

1) Recommendations for specific age-related chronic diseases/conditions that should be considered in the planning for a third NIH Geroscience Summit;
2) Feedback on whether individual organizations may be interested in contributing input to the planning of such a Summit, and areas of interest for participation;
3) Feedback on whether individual organizations may be interested in participating in a summit session that would encompass scientific presentations by public and private stakeholders about the links between specific chronic diseases and geroscience, as well as suggested subtopics for such a session; and
4) Input on the potential impact of this type of session on future scientific needs and progress in regard to specific diseases affected by aging.

More details in this article by Felipe Sierra, Scientific Executive at the NIA’s Division of Aging Biology (DAB) and all-around great guy.

The time to share your ideas is now: the third summit will be held in spring of 2019, but the deadline for the RFI is June 1 (i.e., in two weeks). So, get a move on—share your thoughts with GSIG and share this opportunity widely with your colleagues.

SaveSave

In order to develop anti-aging pharmaceuticals, we need targets—proteins (or other macromolecules) whose functions influence longevity, and whose activities can be modulated by drugs in order to enhance lifespan.

One of the most well-known targets identified to date is mTORC1 (“mechanistic target of rapamycin complex 1”; “TOR” to its friends), which is targeted by the small-molecule drug rapamycin. Inhibition of the TOR pathway by rapamycin extends lifespan and exerts a variety of other beneficial effects in mice. The results to date are so promising that a large-scale test of the drug’s effects is currently underway in domestic dogs. As any dog lover would tell you, extension of canine lifespan is a worthy goal in its own right, but the Dog Aging Project has another selling point: if we can show that rapamycin prolongs life in two fairly diverged mammalian species, we would be much more confident that the drug would work in humans.

Despite the promise of rapamycin, however, there is also a risk of side effects. The compound was originally approved for use as an immune suppressant, albeit at much higher concentrations than those used for lifespan experiments, and it is conceivable that chronic low-dose use could have immunological consequences. Moreover, rapamycin may inhibit the formation, consolidation, and preservation of long-term memory (though again, it’s not certain it would have this effect at lower doses); I don’t have to point out the irony of a longevity-enhancing drug that eroded the memory.

Therefore, it makes sense to identify the specific effectors of TOR (a multifunctional signaling integrator hat influences a great many cellular processes) that govern lifespan and inhibit those.

One attractive candidate for this purpose is the dominant-negative LIP isoform of the transcription factor C/EBPβ. We’ve known for a while that calorie restriction (CR), which extends lifespan, upregulates C/EBPβ but shifts translation from LIP to the beneficial isoform LAP.  Conversely, TOR activity (which is negatively associated with lifespan) increases the relative abundance of LIP, which is also upregulated with age.

TOR does this via a very cute form of translational regulation that requires an upstream open reading frame (uORF) in the Cepb mRNA — the details are a bit beyond the scope of this post, but for now all we need to know is that when the uORF is present, TOR activity boosts synthesis of C/EBPβ-LIP. On the other hand, when the uORF is absent, LIP synthesized is dramatically reduced and LAP is comparatively more abundant..

In previous work, the Calkhoven group at ERIBA showed that elimination of the uORF (causing a decrease in LIP production) in mice mimics the metabolic effects of CR without requiring any reduction in caloric intake. This makes a very strong prediction…which turns out to be true. In their most recent paper, the same group showed that in addition to being more metabolically healthy, the ∆uORF mice also develop fewer tumors, have a more youthful physiology, and live longer than wild-type controls.

The molecular data in the study strongly imply that TOR-induced production of LIP plays a causative role in aging…making LIP  (and more broadly, the regulation of C/EBPβ isoforms) a promising target for anti-aging medicine. This is not lost on the authors, who have already developed a high-throughput screen for compounds that suppress LIP production—potentially enabling identification of CR mimetics that confer the lifespan-extending properties of TOR suppression without risking the side effects of chronic rapamycin exposure.

Müller et al. “Reduced expression of C/EBPβ-LIP extends health- and lifespan in mice.” eLife 2018;7:e34985. DOI: 10.7554/eLife.34985

Efforts to accelerate progress toward anti-aging medicine and longevity enhancement include academic research in public and private institutions, for-profit research institutes, pharmaceutical companies, and non-profit organizations that advocate for more research — and are increasingly funding it themselves.

I just learned of what seems to be another example of the latter category: the Longevity Research Institute, a not-for-profit entity devoted to the extension of the human lifespan. The LRI is based in Berkeley, CA

Here’s how they describe themselves:

Our Mission

There are more than 50 compounds and treatments that have been reported to extend lifespan in mammals, and dozens more that seem to prevent the diseases of aging — yet few of these studies have received independent follow-up or replication.

If we could find a healthspan-expanding treatment for humans, it would prevent years of severe illness for billions of people. […]

Over the next five years, we plan to design, fund, and launch animal lifespan studies for the most promising longevity interventions.

The effort appears to be quite new; Judging from the post dates on their blog, they just launched last week. They’re just across the bridge from where I live, so I’ve reached out via their Twitter account to see if I can meet up with them to learn more.

In the meantime, I wanted to share this very early news with you all.

Let us all welcome LRI to the biogerontology research community!

Research in model organisms has taught us a great deal about the fundamental biology of aging. Our belief in the value of such studies—specifically, the idea that we can learn about human aging by studying longevity in smaller, shorter-lived species— is predicated on the idea of evolutionary conservation: in organisms related by common descent, similar genes do similar things for similar reasons. According to this logic, if a pathway extends lifespan in a mouse, it’s at least worth checking to see if it has similar effects in larger mammals (like us).

But what can we learn from animals with unconventional life cycles? Suppose, for example, that we knew of a species with an exceptional lifespan for its body size. One might seek to identify the differences between that species and shorter-lived species, and then hypothesize that at least some of those features were responsible for the enhanced longevity. However, if the species in question also has an unusual natural history, implying very different selective pressures over the course of its evolution, it might be difficult to parse out which differences are related to lifespan.

This issue confronts one of the most fascinating models for the study of aging: the naked mole rat*, Heterocephalus glaber, a small rodent that can live more than 30 years and (at least by one definition) does not age. Specifically, H. glaber exhibits a rare feature known as negligible senescence: a lack of increase in the mortality rate as a function of time. Adult naked mole rats manifest no age-related decline in physiological functions, rarely develop cancer, and are no more likely to die at 20 years of age than at 5. Naked mole rats express high levels of stress-response gene, including those encoding DNA repair factors and protein chaperones, and it is tempting to speculate that these (or other) distinctive cellular and molecular characteristics of this species hold the secret to long life.

Unfortunately from the standpoint of evolutionary conservation, and the logic outlined in the first paragraph of this piece, naked mole rats are just plain weird. They are finely adapted to their subterranean lives, are capable of withstanding hypoxia for long periods of time, and regulate their body temperatures very differently than other mammals—they’re not quite cold-blooded per se, but they are thermolabile, and can tolerate dramatic swings in core temperature in response to changing environmental conditions. Moreover

Consequently, one is left wondering whether any given distinct property of naked mole rats relative to (e.g.) mice is related to extended lifespan, or simply an adaptation to their unusual life cycle. Similarly, it is conceivable that even the bona fide causal pro-longevity mechanisms in this species only function against the backdrop of the idiosyncratic features that have emerged over millions of years of divergent evolution. Simply put, then: Can we learn about the fundamental biology of mammalian aging, in a general sense, by studying one bizarre mammal?

Happily, based on a new paper from Shelley Buffenstein’s lab (which administers the largest naked mole rat colony in the US and possibly the world, and which recently relocated to the aging research company Calico), the answer appears to be at least a qualified yes.

The authors examined the plasma metabolome (the signature of small molecules in the circulating blood) in naked mole rats, reasoning that prolongevity cellular behaviors would manifest as differences in the metabolic profile. The plasma metabolome is advantageous for studies of this type because it integrates the biochemical activities of many cell types in many tissues, along with dietary conditions and overall health status. Moreover, it can be measured relatively non-invasively, requiring only a conventional blood sample.

The metabolite concentrations in mole rat plasma mirrored changes observed in other rodents subjected to life-extending interventions, such as methionine restriction in rats and calorie restriction or genetic dwarfism in mice. Some of the measurements were even reminiscent of the differences between young and old humans. Together, these findings imply that the pro-longevity cellular maintenance pathways that can be activated by nutritional or environmental signals in all mammals are simply always turned on in mole rat, and that the lifelong activation of these pathways is responsible for this species’ unusual longevity.

Moreover, the results address the question I raised above regarding the suitability of mole rat as a model system in biogerontology. Despite the dramatic differences between the natural histories of mole rats and other rodents, it seems clear that at least some of the key pro-longevity mechanisms are conserved, even extending to primates. Therefore, we should be able to identify lifespan-extending interventions by searching for conditions that make mice—or at least their plasma—look more mole rat–like.

Lewis et al. “A window into extreme longevity; the circulating metabolomic signature of the naked mole-rat, a mammal that shows negligible senescence.” GeroScience 2018 Apr 20 1–17 (epub ahead of print). DOI: 10.1007/s11357-018-0014-2

* Which, for the record, is neither a mole nor a rat.

SaveSaveSaveSave

SaveSave

Funding opportunity for early-stage research in aging: The Oklahoma Nathan Shock Center is soliciting applications to support the research of junior investigators developing R01 applications and senior investigators developing new applications to the NIH in the Biology of Aging. If you’re not in Oklahoma, never fear: applications from institutions outside of the University of Oklahoma Health Sciences Center are strongly encouraged.

The Nathan Shock Centers of Excellence provide leadership in the pursuit of basic research into the biology of aging.

The projects should utilize one or more of the four Cores of the Center, which provides services that can be used to analyze biological samples from humans to invertebrates: Multiplexing Protein Quantification Core, Targeted DNA Methylation & Mitochondrial Heteroplasmy Core, Integrative Redox Biology Core and the Discovery Bioinformatics Core. Prior consultation with the Core Directors is strongly advised.

The awards are for 1 year and are generally between $10,000 and $20,000 depending on the specific needs of the applicant.
Applications are due June 1, 2018
Anticipated Date of Awards: July 1, 2018.
Pilot Study Funding Period: July 1, 2018 – June 30, 2019

Find more information and application details here.

Calorie restriction—limiting the amount of energy consumed by an organism, while ensuring proper nutrition—is among the most reliable ways to extend healthspan in a wide range of organisms. A vast literature has documented the effects of CR (and related approaches such as intermittent fasting) in animals reared in the laboratory, and I have written extensively about them here. However, we still know comparatively little about the benefits of such regimens in human beings.

In some sense, this is unsurprising: humans, near and dear to our hearts though they might be, make lousy model organisms. Even within the same society, we eat differently from one another, exercise differently (or not at all), and live in wildly diverse settings, making it difficult to control for all relevant variables. To compound the problem, we already enjoy long lives—inconvenient indeed if one hopes to observe the effects of dietary changes on lifespan within a reasonable interval of time.

However, this has not stopped intrepid researchers from initiating (and then following through!) on clinical trials of CR in humans. Over the past decade, the first two phases of the cleverly named CALERIE* study showed that fairly drastic, long-termCR is safe and well tolerated in human subjects.   More recently, an ancillary study of the second phase of CALERIE performed a detailed examination of the changes in energy expenditure associated with CR, measuring multiple endpoints, including markers of oxidative stress and aging more generally.

The results, published earlier this month, provide further validation that CR is safe in non-obese human subjects. Although the data are too preliminary to tell us whether CR extends lifespan in humans, they are consistent with previous findings in model organisms, suggesting that (subject to heavy qualifications, and limited by the the temporal scope of the study) CR may also work in people.

The measurements the authors made help us understand how it might work — and the results have ramifications for two prominent theories of aging.

The participants in the study lost weight (unsurprisingly), but their overall energy expenditure decreased even further, significantly more than would be predicted from the decrease in body mass. This is in line with the predictions of the “rate of living” hypothesis, which states (to massively simplify) that lifespan is inversely proportional to metabolic rate. In these human subjects, CR decreased energy expenditure per unit mass, an indicator of the metabolic rate — so, if it eventually turns out that CR extends lifespan in humans (which, again, we don’t yet know), it could be doing so by inducing a metabolic adaptation.

The CALERIE subjects also had lower levels of oxidative stress, as revealed by measurements of a panel of molecular markers. The authors argue that this observation supports the well-known “free radical theory of aging” (FRTA)†, which holds that aging could be caused by endogenously generated oxygen radicals. We could interpret the data as showing that CR decreases reactive oxygen species (ROS) production (possibly, but not necessarily, by decreasing the overall metabolic rate). Thus, if CR also extends lifespan, it may also achieve this end by lowering the oxidative stress burden.

However, an alternative interpretation is available. The FRTA is one of the oldest modern theories of aging, and has undergone numerous rounds of attack, defense, and revision. On this topic, my own thinking has been been heavily influenced by a fantastic review by Siegfried Hekimi, which attempts to reconcile the large body of circumstantial evidence implying a causative link between oxidation and aging with a growing body of genetic and biochemical evidence that it does not. We can synthesize these two apparently contradictory positions by positing that under most circumstances, oxidative molecules such as ROS are not causes of aging, but instead act as second messengers to signal other kinds of stress that actually do contribute to the aging process. From this standpoint, we would still expect to see a reduction in the levels of oxidative markers in a person who was aging more slowly, but we would not conclude that the decrease in ROS levels was causally responsible for slower aging per se.

How the effects of CR in humans influence our thinking about the causes of aging will ultimately depend on whether CR actually extends longevity. On that issue, the first primate past the post will be not H. sapiens but M. mulatta, We know that CR confers health benefits in macaque, but the final lifespan data are still pending. Given the close evolutionary relationship between great apes and Old World monkeys , we can be fairly confident that if CR extends lifespans in macaques, it will also do so in humans.

In the meantime, however, there are no red flags in the human data, and the results to date seem promising. So far, so good. Watch this space for future developments—in 20 years or so, we’ll have some lifespan data for you.

Redman et al. “Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging.” Cell Metabolism 27(4):805–815 (2018). DOI: 10.1016/j.cmet.2018.02.019

* Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy. I’m inclined to forgive the misspelling, but would “Outcomes” have been so bad?

† Sometimes called the mitochondrial free radical theory of aging (MFRTA), which evokes fewer giggles from Scrabble fans than FRTA.

SaveSaveSaveSaveSaveSave

From the mailbag — the National Institute on Aging is sponsoring a week-long summer training course on biogerontology, to be held at the Buck Institute for Research on Aging in Marin County, just north of San Francisco.

It should be an excellent course, although the application process is likely to be competitive — spots are limited, and the course is completely free including travel.

Applications close April 13th. Full details here:

The Summer Training Course provides intense exposure to current concepts in experimental aging research for 15-20 research scientists. It is designed primarily for junior faculty and advanced fellows with at least two years postdoctoral experience in cell or molecular biology or a related field. Senior scientists who wish to learn about current aging research are also welcome to apply.

Each day includes: i) overview lectures on a pivotal topic in modern aging research; ii) development workshops at which trainees present a research proposal, which will be critiqued by workshop faculty with aging expertise; iii) faculty research talks on selected topics. Faculty for the 2018 course include some of the world’s leading scientists in the aging and longevity research community.

A new set of FDA draft guidelines for assessing Alzheimer’s disease (AD) drugs could accelerate approval of early interventions against this devastating disease. More broadly, the new rules have intriguing ramifications for drugs targeting aging and longevity in humans.

The challenge of developing effective AD medications is severe: the disease advances invisibly for years before symptoms are clinically detectable, and the earliest signs are subtle and variable among patients. By the time unambiguous symptoms emerge, neurons have died en masse, and countless brain circuits have been disrupted. Even if we could stop the progress of the disease at that point, the damage is irreversible.

Making matters more difficult, the historical criteria for enrollment in AD clinical trials have been very stringent: the FDA required that eligible patients have both cognitive and functional impairment (i.e., defects in thought as well as difficulties performing daily activities). Furthermore, to be considered efficacious, a drug had to be able to improve both types of endpoints.

These demanding conditions may underlie the failure of multiple trials of promising medications: In clinical trials initiated after the onset of dementia, antibody therapies such as bapineuzumab and solanezumab have successfully decreased Aβ aggregation in the brain, but did not lead to effective recovery from dementia symptoms. Consequently, despite the favorable molecular outcome, the trials had to be considered failures—possibly because the interventions simply came too late, after the damage was done.

Acknowledging that progress toward pharmaceuticals capable of treating complex neurological conditions has been “uneven,” the FDA has proposed revising its guidelines for trials aimed at early AD (link):

The FDA has been working closely with patients and the scientific community to gain the knowledge that will support intervention in very early AD in ways that have the potential to stop the disease before it causes clinical problems. This document describes innovative approaches to studying very early disease before the onset of dementia, including strategies for trials incorporating patients with Alzheimer’s who haven’t experienced any visible impairment (in the form of cognitive or functional deficits), but who may be identified through the use of sensitive cognitive screening, imaging tests, or biomarkers.

The new draft guidelines, which you can read in their entirety here, update the FDA’s thinking on AD treatment to reflect the most current understanding of this illness.

To overcome some of the obstacles created by the stringency of the previous criteria for efficacy, the new guidelines abolish the cognitive/functional dichotomy and allow that cognitive improvements are independently importance in their own right.

More importantly in regard to the earliest stages of AD, the new rules open the door to drugs whose primary endpoints are neither cognitive nor functional in nature, but instead are “biomarkers” — serological or radiological measurements that reflect the pathophysiological changes that precede even the sublest neuropsychological symptoms. On the assumption that these molecular changes precede AD symptoms because they are causative, treatments capable of normalizing AD biomarkers in presymptomatic patients have the potential to delay disease progression or prevent it altogether.

If the FDA is willing to consider biomarker endpoints for a complex, age-related condition such as AD, it could set a valuable precedent for how to assess drugs aimed directly at the aging process. The logistical challenges confronting clinical trials of anti-aging medications are staggering, exacerbated by the controversies surrounding endpoint selection. Mortality, functional status, and time-to-event (e.g., onset of age-related disease, as proposed for the TAME trial) have all been considered as endpoints, but each has its own logical and practical disadvantages, not least of which is the time required to make the necessary observations. If we could evaluate drug efficacy by monitoring the real-time effect on well-established biomarkers of aging, it could dramatically accelerate the testing and approval of longevity-enhancing compounds.

Currently, the new guidelines are under review as the FDA collects feedbacks from patients, researchers, and industry. Presumably, a favorable response from clinician researchers and pharmaceutial industry will increase the likelihood that the guidelines will be formally adopted.

Across a wide range of organisms, levels of the key metabolite NAD+ decline with aging, with undesirable consequences at multiple biological scales: In our cells, reduction in NAD+ decreases the activity of the sirtuins, a well-characterized family of pro-longevity proteins. At the systems level, the changing NAD+/NADH balance interferes with the communication between our brains and adipose tissues, resulting in further metabolic dysregulation.

Consequently, a fertile and active area in the broad field of longevity enhancement is the concept of NAD repletion: the idea that, by supplementing the body with molecules that help cells make more of this compound, we can restore (or at least maintain) a more metabolically youthful state, from the cellular level on up.

At present, NAD repletion lies at a busy intersection between basic research, the nutraceutical industry, and translational medicine: A growing number of fundamental studies have demonstrated that supplementation with NAD precursors extends lifespan (and boosts its cellular- and tissue-level correlates) in mice; related compounds are being marketed direct to consumers without FDA regulation; and the first clinical trials are beginning to assess whether we can safely and sustainably increase NAD+ levels in humans.

Because the human data are so preliminary, much of our belief in the potential for NAD repletion relies on results from animal models. Accordingly, it behooves us to keep abreast of the most recent developments. This is especially true when the latest results are partially, but not completely, consistent with previous findings; such discrepancies can reveal cracks in our models and blind spots in our understanding of critical biology.

In the most recent issue of Cell Metabolism, Mitchell et al. report that administration of nicotinamide (NAM), a precursor of NAD+, confers a variety of benefits. In a mouse model, the authors demonstrated that NAM treatment decreased oxidative stress, improved glucose metabolism, and prevented age- and lifestyle-related deterioration of the liver. The supplemented mice benefited at a functional level as well, exhibiting improved coordination and locomotor activity. Thus, NAM (like other NAD+ precursors) increased the ‘healthspan’, that is, the proportion of the adult lifespan free of age-related disease.

Despite these benefits, and in contrast to other NAD repletion studies, NAM treatment had no effect on mean or maximum lifespan, implying that the improvements observed in functional studies occurred in pathways that are not limiting for lifespan, at least in this strain of mouse. Moreover, while there was some evidence that sirtuins were activated, tissue levels of NAD+ did not measurably rise.

This is surprising, given that other NAD precursors have been shown to both extend lifespan (and, for that matter, boost NAD+ levels as expected)— raising the question of why NAM, an orally bioavailable NAD precursor, does not have the same effect. One possible explanation, supported by the authors’ findings in this study, is that NAM administration suppressed uptake of NAM and altered expression of NAD biosynthetic enzymes, although it remains less than clear why this would yield some, but not all, of the previously observed benefits of NAD repletion. Alternatively, high doses of NAM could be inhibiting sirtuin activity, as they do in yeast—but given that NAM is itself produced by enzymes that consume NAD, it is not clear why all methods of NAD repletion would not run afoul of this type of end-product inhibition.

For me, the key point is that there was a strong prior reason to believe that NAM supplementation would have the same healthspan- and lifespan–extending benefits as other NAD precursors…but it didn’t, which means that we still have a good bit left to learn about the biology of the NAD pathway, even at the fairly simple level of how to inject material into the system to adjust relative concentrations of compounds of interest in a safe, salutary, and sustainable way.

Mitchell et al. “Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice.” Cell Metabolism 27(3):667–676 (2018). DOI: 10.1016/j.cmet.2018.02.001

SaveSave

I elected to speak about the coming era of anti-aging medicine, first giving some short background on the fundamental biology of aging and then talking about some of the challenges and opportunities presented by clinical progress in this field.

The presentation went off without a hitch, and I got a tremendous amount of feedback from Long Now members about the talk. It was especially exciting to find out about the topics that non-scientists wanted to learn more about, and this will inform my research on future projects on this topic.

At some point I’m going to put a transcript and all the slides on Medium, but that won’t happen for another week or so.

P.S.: Notwithstanding the MC’s pronunciation, my last name rhymes with “hill,” not “eel”.

SaveSave

From the mailbag, news of a new aging-related peer-reviewed journal, currently in its first issue: Pathobiology of Aging & Age-related Diseases. I haven’t had to check it out yet, but it looks like it will be of broad interest to biogerontologists from a variety of disciplines. The editorial board includes quite a few luminaries of the field, so it seems promising.

In their own words:

Aims: Pathobiology of Aging & Age-related Diseases (PBA) is a new peer reviewed journal serving as a forum for researchers to communicate pathology data as a primary scientific focus of aging; data that might be of less interest in other journals more focused on generic aging or specific scientific disciplines. We are especially interested in developing a focus for advancing the pathological basis of aging in mammalian systems, in particular the mouse and humans.

Scope: Pathobiology of Aging & Age-related Diseases is interdisciplinary in nature and covers all aspects of pathology of aging related to disease phenotypes including cancer, cardiovascular disease, neurological disorders, metabolic dysfunction, renal and gastrointestinal disorders, endocrine dysfunction, musculoskeletal conditions and skin disorders. The underlying theme is based on the sound scientific principles of the pathogenesis of aging and age-related diseases as well as intervention data with resolution of pathological endpoints. The emphasis will be on preclinical studies as well as clinical studies related to strategies developed in animal models and will be image intensive. Papers on the basic biology of aging in invertebrates will not be considered unless comparative mammalian data is also included.

We welcome Research papers, Review articles, Brief reports, Case reports, New animal models, Technical reports, Images, PhD thesis Summaries, and Commentaries.

Target groups: Anatomical and molecular pathologists, gerontologists, geriatricians, transgenic mouse geneticists, toxicologists, and scientists, veterinarians and physicians focused on basic and clinical research in cardiovascular disease, cancer, gastrointestinal disease, endocrine disorders, metabolic dysfunction, renal disease, neurological disorders including Alzheimer’s disease, skin disorders, and musculoskeletal disease.

PBA is open-access; the publisher, Co-Action Press, is a relatively new entity whose small but growing stable consists entirely of open-access journals spanning a wide range of fields.

My personal feeling is that there are probably already too many journals, mostly because I don’t think I or my colleagues actually interact with journals as entities. Mostly we just do literature searches, and choose papers to read based on titles and abstracts. The exception is when we’re submitting papers, but then the diversity of formats and author requirements creates obstacles to rapid submission (and re-submission, if necessary).

I wouldn’t mind seeing individual journals be replaced by a robust tagging system on a relatively laissez-faire neo-journal such as PLoS ONE (to allow scholars to create communities and filters on the firehose of new papers), and a little time spent teaching everyone how to set up PubMed RSS feeds. That said, if we’re going to start new enterprises, this is probably the right way to go, so good luck to PBA.

From the mailbag:

You are kindly invited to the Baltic Sea, for the

*RoSyBA: Rostock Symposium on Systems Biology and Bioinformatics in Ageing Research*
15th-17th September 2011 (Rostock, Germany)

Confirmed speakers: Stuart Kim (Stanford), Ann Brunet (Stanford), Jan Hoeijmakers (Rotterdam), Günter Lepperdinger (Innsbruck), Aubrey de Grey (Cambridge), Joao Pedro de Magalhaes (Liverpool), Thomas von Zglinicki (Newcastle), ….

URL: http://goethe.informatik.uni-rostock.de/ibima/rosyba2011/

Early Registration: until June 15, 2011 – Save up to 100%
Call for Contributions: deadline June 1, 2011

I am writing to inform you that June 15th is the deadline for
discounted registration and abstract submission for the fifth
Strategies for Engineered Negligible Senescence (SENS) conference, to
be held at Queens’ College, Cambridge, England on August
31st-September 4th 2011. After the deadline, all registration fees
rise by £150.00. Also, after that date, we cannot guarantee that
submitted abstracts will be considered for oral presentation or that
they will be included in the conference abstract book.

All details of the conference, including forms for abstract submission
and online registration, are at the conference website:

http://www.sens.org/sens5

The conference program features 33 confirmed speakers so far, all of
them world leaders in their field. As with previous SENS conferences,
the emphasis of this meeting is on “applied gerontology” – the design
and implementation of biomedical interventions that may, jointly,
constitute a comprehensive panel of rejuvenation therapies, sufficient
to restore middle-aged or older laboratory animals (and, in due
course, humans) to the physical and mental robustness of young adults.
The list of sessions and confirmed speakers is as follows:

SENS Lecture:
Caleb Finch, ARCO/Keischnick Professor of Gerontology and Biological
Science and Director, Gerontology Research Institute, U. Southern
California
Decellularised organs for tissue engineering
Shay Soker, Laura Niklason
New advances in stem cells
Xiao-Dong Chen, Mariusz Ratajczak
Gut rejuvenation
James Wells, Graca Almeida-Porada
Brain aging
David Rubinsztein, Einar Sigurdsson, Charles Greer, Rodolfo Goya
Combating mitochondrial mutations
Matthew O’Connor, Michael Teitell
Genetic dysregulation in aging
Silvia Gravina, James Kirkland
Cancer
Minoru Ko, Bill Andrews, Dan Kaufman, Michael Lisanti
Novel treatments for atherosclerosis
Pedro Alvarez, Alexandr Kharlamov
Crosslink accumulation in the extracellular matrix
Daniel Nyhan, Paul Thornalley, David Spiegel
Novel antibody technology
Kenneth Shea, Michael Sierks
Immunorejuvenation
Janko Nikolich-Zugich, Doren Melamed
Bioinformatics in aging
Alex Zhavoronkov, Pat Langley, Maria Konovalenko
The long-term context of truly effective medicine aginst aging
Max More, Dana Goldman

In addition, there will be at least twenty short talks selected from
submitted abstracts, as well as poster sessions each evening. Authors
of short talks and posters will, like the invited speakers, be invited
to submit a paper summarising their presentation for the proceedings
volume, which will be published in the high-impact journal
Rejuvenation Research early in 2012.

Please note that registration fees are fully inclusive of
accommodation and all meals. Those not requiring accommodation,
journalists wishing to obtain free press passes (not including
accommodation), and those who are unable to register using a credit
card are asked to contact me by email (aubrey@sens.org).

I hope to welcome you to Cambridge in August!

Cheers, Aubrey

Aubrey de Grey
Organiser, SENS5
Chief Science Officer, SENS Foundation
Editor-in-Chief, Rejuvenation Research

Talks in this session:

1. Sagi: Engineering a long-lived worm
2. Suchanek: The germline and somatic reproductive tissues influence C. elegans
3. Stanfel: Ribosome Function and Aging

Dror Sagi (Stanford; Kim lab) — Engineering a long-lived worm

If aging is an engineering problem, then we should be able to solve the engineering challenges more easily in simple systems.

By introducing genes from a long-lived organism into the genome of a short-lived organism, it should be possible to add pro-longevity functions – in effect “upgrading” the short-lived animal so that it lives longer. Sagi has set out to do just that, by transferring genes from the long-lived zebrafish (4-year lifespan) to the short-lived work (4-week lifespan).

The first gene he described was the UCP2 gene, the subject of an earlier talk. Expressing fish UCP2 in the worm lowers overall ATP, and extends worm lifespan. As an important control, expressing an additional copy of the worm UCP2 under the same promoter control does not extend life.

Likewise, fish lysozyme results in lower daf-16 activity, and also extends lifespan. The fish enzyme appears to act by decreasing the pathogenesis from E. coli, an unnatural food source for the worm that causes health problems in late life.

Overall, Sagi characterized 5 well-characterized longevity pathways, testing 16 genes and getting 7 hits.

The next obvious question: Can “upgrade” genes be combined to further increase lifespan? Indeed they can: several pairwise combinations of genes combined to extend lifespan longer than either single gene alone. At some point it worked a little to well: the lifespan of the worms started getting long enough that the survival curves became unwieldy.

• Staying with the worm…

Monika Suchanek (UCSF; Kenyon lab) — The germline and somatic reproductive tissues influence C. elegans

Classically, it had been assumed that there is a tradeoff between lifespan and the number of progeny produced over the lifespan. We now know that this isn’t necessarily true; there are several examples of long-lived mutants that have a normal number of progeny (though the kinetics may be slower, which poses an issue with respect to fitness: if I live twice as long as you and have the same number of progeny but half as quickly, I will probably lose the evolutionary race).

Suchanek began by reviewing old data (like, from when I was a rotation student in the Kenyon lab: old) demonstrating that removal of the germ cells results in lifespan extension, but that this longevity enhancement requires the presence of the somatic gonad. This loss of the germline causes nuclear accumulation of the DAF-16/FOXO protein in the intestine. It is clear from several diverse pieces of data that the somatic gonad and germ line exert their effects on longevity somewhat independently.

Two other genes, daf-9 and daf-12 are required for the extended longevity of germline-deficient worms. DAF-9 is an enzyme that makes dafachronic acid, the ligand of a receptor encoded by DAF-12. Addition of dafachronic acid has no effect on lifespan of germ-cell-deficient, somatic-cell-competent cells, but it does extend the lifespan of animals that lack both germ cells and the somatic gonad.

How does the intestine know that the germ line is gone? To answer this question, Suchanek screened a “signaling sublibrary” of 1304 genes, and got 115 unique hits including several components of the Wnt pathway. Two components, mom-2 and wrm-1 (ß-catenin), are required for nuclear accumulation of DAF-16/FOXO and for the extended lifespan of germline-deficient worms. Suchanek favors a model in which germ line cells emit Wnt inhibitors.

• Finishing on a strong note…

Monique Stanfel (Buck Institute; Kennedy lab) — Ribosome Function and Aging

The Kennedy lab is interested in identifying longevity/aging genes that are conserved in yeast and worm, and then testing these in the mouse.

In both yeast and worm, deletion/knockdown of many ribosomal proteins (RPs) can extend lifespan. In yeast, most if not all of the RPs with a role in lifespan are components of the large subunit (60S). In worm, knockdowns of both small and large subunit components can increase lifespan. Three of the genes conserved between worm and yeast can be knocked down in mice.

In order to characterize translation in mouse mutants, Stanfel ran polysome gradients on liver tissue. She analyzed the fractions in two ways, looking at both ribosome-associated RNAs and at the ribosome-associated proteins.

Surprisingly, the Rpl22 gene can be knocked out and has very little effect on global translation in the mouse liver. This may be because a homologous gene, Rpl22L (“-like”) is compensating for the loss of the major species.

Knockout of another gene, Rpl29, has a larger effect on global translation, decreasing the levels of 80S ribosomes. When fed a high-fat diet, Rpl29 knockouts were protected against weight gain, and their blood glucose also remained low; furthermore, the animals were leaner than wildtype. They also resist developing cardiac hypertrophy in another assay – thus, they meet all the preliminary criteria for the time and resource investment of a lifespan study.