We know that exercise is good for us, and increasingly we’re understanding how it works at the molecular and cellular level: Physical activity boosts levels of heat shock proteins, which help cells resist stress; it also improves mitochondrial function in a manner reminiscent of calorie restriction (CR). Our knowledge is sophisticated enough that we can identify and develop small-molecule exercise mimetics and drugs that improve exercise tolerance.

Overall, then, exercise and its molecular/cellular consequences are consistent with longevity assurance pathways and life extension interventions. However, there are complications emerging.

One of the results of exercise is increased activity of anabolic pathways, especially in muscle. Building up tissues require new protein synthesis, and new protein synthesis requires activity of the TOR pathway. TOR is increasingly thought to be a pro-aging or gerontogenic pathway: rapamycin, a drug that inhibits TOR, blocks senescence and extends lifespan in mice (we already knew that TOR inhibition increased longevity in worms and yeast).

Until recently, we’d believed that exercise modulated TOR in the “right” direction for longevity assurance (i.e., down). For instance, AMPK, a target of exercise mimetics, appears to downregulate TOR signaling.

But it would appear that the above result, obtained using exercise mimetics, may not be generally applicable to all exercise — in particular, it does not extend to a specific regimen of exercise designed to stimulate anabolism and muscle growth. In blood flow restriction (BFR) exercise, resistance training is combined with pressure cuffs that significantly decrease blood flow to the exercising muscle; it increases protein synthesis in muscle cells and activates the TOR pathway. Now, Fry et al. have shown that in older men (who don’t increase muscle mass in response to ordinary resistance training), BFR activates TOR.

Superficially, this would seem to represent a contradiction: a lifespan-extending intervention (exercise) activates a lifespan-shortening biochemical signaling pathway (TOR). How might this seeming paradox be resolved?

  • TOR activity in the muscle might be irrelevant to lifespan control. Testing this hypothesis is a special case of a broader question, which is the determination of the key tissues responsible for the lifespan extension by rapamycin. This will probably require tissue-specific conditional knockdowns of either TOR or downstream pathways (e.g., S6K), and will take a while.
  • Not all exercise is lifespan-extending. Perhaps exercise regimens specifically optimized to stimulate anabolism might be gerontogenic, while those that create acute stress and activate hormetic pathways might extend lifespan.

It’s also worth mentioning that BFR exercise may be uniquely bad vis-a-vis longevity control. In worms, one of the targets of TOR is HIF-1, the hypoxia inducible factor. HIF-1 is a gerontogene: knocking it down extends longevity, so its wildtype function must shorten lifespan. I wonder whether the blood flow restriction in BFR exercise might create low-grade hypoxia in the muscle tissue, inducing HIF-1 activity and incurring some gerontogenic effect. It certainly wouldn’t be the first time that an intervention that helped older men increase muscle mass ended up being bad for them in the long run (e.g., hGH).

ResearchBlogging.orgFry, C., Glynn, E., Drummond, M., Timmerman, K., Fujita, S., Abe, T., Dhanani, S., Volpi, E., & Rasmussen, B. (2010). Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men Journal of Applied Physiology DOI: 10.1152/japplphysiol.01266.2009

Add to FacebookAdd to DiggAdd to Del.icio.usAdd to StumbleuponAdd to RedditAdd to BlinklistAdd to TwitterAdd to TechnoratiAdd to Yahoo BuzzAdd to Newsvine

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.







Stem cells:


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!



DNA damage & gene expression:





TOR signaling:


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.

For those who were intrigued by yesterday’s post about the reversal of dermal aging by blockade of NF-κB, I wanted to point our a few more interesting tidbits related to everyone’s favorite inflammatory transcription factor.

  • Skin is not the only organ in which aging can be reversed by attacking NF-κB activity. In the immune system, Huang et al. report that pharmaceutical inhibition of NF-κB blocks age-related increases in inflammatory cytokine production. The study focuses on a class of helper T cells that have been implicated in both immune senescence and autoimmune pathologies.
  • Mourkioti and Rosenthal review the role of NF-κB in muscle, and discuss several mechanisms by which the factor might influence age-related muscle disease.
  • Finally, Li et al. demonstrate that the MULAN protein is a mitochondrial ubiquitin E3 ligase that regulates mitochondrial dynamics. Prior work had shown MULAN to be an activator of NF-κB, so this study may be the first step toward establishing a novel signaling pathway between the mitochondria and the nucleus. (Brainstorming topic: Under what conditions would the mitochondria want to instruct the nucleus to produce inflammatory cytokines?). Their paper is at PLoS ONE, so reader comments are welcomed.

Sarcopenia (muscle wasting) is one of the most devastating aspects of the frailty syndrome that accompanies old age. Ryall et al. have a review of the molecular and cellular mechanisms underlying age-related degeneration of skeletal muscle.

The argument about the physiological relevance of oxidative stress and mitochondrial aging rages on. From Figueiredo et al. comes a general mitochondrial oxidative stress review, with a focus on muscle:

There is strong evidence pointing out an age-related increase in the levels of oxidative stress and oxidative damage continuously imposed on mitochondrial biomolecules, which becomes progressively more apparent with advancing age. Since the cellular capacity for repair is not completely efficient, this increased damage might lead to accumulation of dysfunctional proteins, impaired membrane integrity and increased levels of mutant mtDNA, which will proliferate in an irreversible way by means of mitochondrial and cellular division. Consequently, the number of redundant components of intact mitochondria will be reduced, compromising the maximal mitochondrial function and consequently the maximal energetic capacity of skeletal muscle fibers.

The authors propose that, while mitochondria that accumulate some damage often retain sufficient function to operate at basal levels, operation under conditions of stress might tax the aged system beyond the functional capacity to 1) produce energy sufficient for demands and/or 2) efficiently cope with the increased oxidative stress burden of acute stress.

Okie here, back from the SENS3 conference in Cambridge, and slowly recovering from jet lag.

General thoughts: As a scientist, it is a challenge to present my work to a mixed group of scientists and (particularly well-educated) lay people. Where translational research is concerned, however, I think that lay people do a great job keeping us researchers focused on the prize and not just on (interesting) esoteric points.

As in my previous conference reports (see here and here) I will cover general themes of the meeting, as well as summarizing specific presentations that I found most interesting. Unfortunately I can’t cover them all; what I decide to cover is purely subjective and perhaps even a bit arbitrary. Also, I may skip or gloss over talks/themes that were repeated from the Edmonton conference with little progress.


Biomedical remediation

The fascinating field of biomedical remediation (essentially the brain-child of Aubrey de Grey) is moving along quickly. We heard from two collaborating/competing groups: Pedro Alvarez from Rice and John Schloendorn, a student from Tempe, Arizona being supported directly by the Methuselah Foundation. Pedro is a brilliant environmental chemist/bioremediation guy turning some of his talents on the biological problem of lipofuscin accumulation. The work is progressing rapidly. Both teams have identified strains of bacteria capable of using 7-ketocholesterol (one precursor of the poorly defined lipofuscin) as energy. The next goal is to clone the genes. After that they want to purify the enzyme responsible and feed it to people and see if it will break down our lipofuscin.

My only criticism isn’t with the method, results, or rate of progress (which are all fantastic). My issue is that they are trying to solve a problem that hasn’t been proved to be a problem yet. Lipofuscin accumulation has long been associated with aging in many tissues, but never (as far as I am aware) proved to be responsible for any illness, ailment, or disease. Now, don’t get me wrong, Aubrey makes an excellent argument for this being a serious problem with no traditional biomedical solution in sight, but it’s still just theory. As one of my old mentors used to say, “In this game you’ve got to have data!” Here’s my 2 cents: Now that they’re homing in on the genes, how about cloning the gene and making a transgenic mouse? Might be easier to look at toxicity, long-term affects, and efficacy with a transgenic; though dosage control is problematic with transgenics.

Wound Healing/Artificial Repair

In my opinion, this was the most provocative and promising aspect of the research at SENS 3. Really cool stuff below.

Cato Laurencin is an amazing individual. He is one of those rare clinicians who can aim high-quality research directly at clinical applications. He calls his approach “regenerative engineering.” As I work in a bioengineering department, I sit through a lot of boring biomaterials talks. It was amazing, however, to see someone actually using a few in something practical! In my opinion, this is the reality of regenerative medicine: an innovative surgeon combining technology and knowledge of biology to partially repair injuries such that they will heal as well, or better than they started. Dr. Laurencin showed results from his work on 3D absorbable poly L-lactide (PLLA) scaffolds that seem to promote recovery from surgery much more efficiently than traditional methods. This is a microsphere-based scaffold, which promotes efficient invasion and engraftment of osteoblasts to help repair bone. He is also investigating surfaces with nano-scale grooves, which are more conducive to mesenchymal stem cell proliferation.

Rutledge Ellis-Behnke spoke on his work with SAPNS: Self Assembling Peptide Nanofiber Scaffold. Essentially, he squirts a solution containing these nanofibers into wound sites and reportedly achieves amazing results. He reports dramatic recovery from serious brain injury: both scarless repair of bulk brain tissue removal and reinnervation. In addition, he claims that the nanofibers can dramatically stop bleeding in wounds (he showed video of this). These results are so dramatic that they are almost unbelievable. There are some videos attached to this paper that are pretty darn amazing. The mechanism of action is unknown.

Right along these lines, Robin Franklin gave an interesting talk about myelin repair/regeneration. To summarize the take-home message: the presence of differentiated tissue/cells/debris inhibits efficient re-myelination. If they inhibit clearance of dead myelin by artificial or natural means, re-myelination does not occur. The real trick now is to figure out how to stimulate clearance of damaged myelin (especially in old animals), and the holy grail will be to discover which factor(s) in the damage/differentiated tissue inhibit regeneration.

Muscle aging

Two groups and three speakers addressed the issue of aged muscle, muscle regeneration, and muscle stem cells.

Gillian Buttler-Brown summarized her previous work on human cells, establishing that myoblasts (muscle progenitors) senesce in culture and that cells from old people senesce slightly faster than those from young donors. Interestingly, she showed preliminary work analyzing the “secretome” of myotubes generated from old or young myoblasts. This was inspired by the work of the Campisi lab on the secretome of senescent cells.

Michael Conboy summarized the recent work from the Conboy lab showing how old muscle stem cells can be revitalized after being exposed to a young systemic environment and how embryonic stem cells can have a similar paracrine affect on revitalizing old muscle cells. He then described his recent work on asymmetric cell division in muscle stem cells. Basically, the stem cells tend to divide so that the original copy of the DNA stays with one daughter cell and the newly synthesized DNA segregates with the other daughter cells. This ensures that some stem cells remain behind with original copies of the DNA (which are presumably of higher fidelity).

Another talk from the Conboy lab (by yours truly) was a short study on the telomere regulation of muscle stem cells. Basically, we discovered that truly pure, undifferentiated muscle stem cells (satellite cells) have very high telomerase activity. Furthermore, they continue to fully maintain their telomerase activity and telomeres with age. This supports the idea that muscle stem cells remain intrinsically young, even while their tissue ages around them.

Other topics

If you’re not already familiar with Sangamo, I highly suggest you check out this exciting young company. This isn’t garden-variety gene therapy – it’s gene editing, for lack of a better word. It’s not introducing exogenous DNA into your cells, it’s editing your genomic DNA. Right now (since gene therapy doesn’t work) the best approaches (in my opinion) involve ex vivo manipulation of cells (and the immune system is the most amenable to this approach). As you can imagine, this technology could also be extremely useful for cell culture lab experiments. No more need to create knockout mice just to generate knockout cells. You can do it with many cell types and should work in any species. Right now it is ridiculously expensive to have them generate a cell line for you (I heard $20k a while ago), but they just made a deal with Sigma to start selling the tech to labs, so I figure they are planning on making it large-scale and affordable to researchers. What I would like to hear are ways to apply this tech to make cells better, in addition to curing diseases (like AIDS).

There is an NIA project to test various compounds on the lifespan of mice. No real results are available yet, but if you have a favorite drug, vitamin, or supplement of any kind then you too can recommend that it be tested on mice! Randy Strong of UT-San Antonio gave this presentation.

A great disappointment to me was the cancellation of Rita Effros’ talk. A rather, um, interesting talk was pulled together at the last minute to replace her. A gentleman from a small company collaborating with Geron is selling a “nutraceutical” which is supposedly a potent activator of hTERT expression. For the low, low price of $25k per year, you too can extend your telomeres. They are avoiding FDA regulation by calling it a nutraceutical instead of a drug and by NOT doing any clinical trials. I find it ironic that it’s possible to escape regulation by not doing any testing to ensure its safety. They don’t know what tissues the drug nutraceutical is targeted to. About a dozen clients have been taking the compound for 3-9 months. They report extension of mean telomere length of granulocytes (but not yet other immune cells) and an improvement in vision. There are no placebos or negative controls of any kind (controls would make it an experiment, which would make it a drug). Honestly, I’m really glad that there are people out there willing (desperate enough) to do this sort of self-experimentation and I’m anxious to see the long-term results.

Ruth Itzhaki has made an interesting connection between Alzheimer’s disease and herpes virus infection. According to her results, people with the APOE4 allele and an HSV1 infection (that’s the “kissing disease” with which 90% of people are infected, not genital herpes) were more likely to develop symptoms of Alzheimer’s, and more severe symptoms, than patients with the APOE4 allele alone. She finds that viral load is concentrated in AB plaques and speculates that one HSV1 glycoprotein has a similar structure to the AB protein. Finally, she finds increased phosphorylation of Tau protein after HSV1 infection. Currently, no HSV1 vaccination is approved for use in humans…

Zheng Cui (Winston-Salem, NC) is a man with a mission to cure cancer. You may have heard about his method before: it’s a sort of brute force immunotherapy approach. He isolates white blood cells from a donor and injects them into the “patient” (in most cases a mouse). The granulocytes then attack the tumor and “cure” the cancer. One drawback from this type of therapy is that it requires 10 donors for every recipient. He has done some human work and human granulocytes definitely do the job in vitro.

These are just a sampling a lot of fantastic talks and I wish I had time to write about all of them. The videos of all of the talks will eventually be posted online and I urge you to check them out when they become available at the conference website. There were also a number of talks of questionable scientific quality or virtue. I like to think that the field of aging science is separating from the age-old snake-oil stereotypes, but there was definitely a fair amount of what I would term “pseudo-science.” You can check those talks out too.

On a final note, I would like to make a comment about the state of the art. I would like to see more theoretical and statistical work on which problems of aging are the most pressing/serious ones. I think Aubrey’s “7 deadly things” is a well thought out plan for tackling the problem of universal aging. What I would like to see is some data on which problem(s) are rate limiting. For example, what if solving the problem of “too few cells” (cell death and senescence in aging) would double human lifespan all by itself while all the others put together would barely accomplish the same? The keynote talk (by Ryan Phoenix) included some modeling of how soon SENS treatments could be available, how soon we would need to solve the 7 things in order to treat people alive today, and how often treatments would need to be repeated. This all relied, however, on the assumption than all 7 deadly things were created equally. Everyone agrees that we should take steps to provide the most immediate benefits to humankind, but no one agrees on what these are.

In closing: The humorous poster of my friend and fellow conference attendee George Hinkal, who helped with this piece by encouraging me to add a couple things and helping to clarify a couple others.

Next Page »