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

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In my last post I reviewed a paper that provided support for the use of leucocyte telomere length as a proxy for telomere length in the vasculature, concluding that adjustments for factors previously reported to impact on telomere length are critical in association studies. Of course there is always the possibility that some other, as yet unstudied, factor will play a pivotal role. So it is, perhaps, unsurprising that a recent paper, published by a group headed by Elizabeth Blackburn, points to telomerase as a major player. 

Telomerase is the enzyme responsible for extending telomeres, but telomerase activity in peripheral blood mononuclear cells (PBMCs) is low, and until now it has never been examined in a longitudinal study. This pilot study, published in Lancet Oncology, examined the effect of three months of lifestyle changes on telomerase activity.

Increased telomerase activity and comprehensive lifestyle changes: a pilot study

BACKGROUND: Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. Telomere shortness in human beings is emerging as a prognostic marker of disease risk, progression, and premature mortality in many types of cancer, including breast, prostate, colorectal, bladder, head and neck, lung, and renal cell. Telomere shortening is counteracted by the cellular enzyme telomerase. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). METHODS: 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. 24 patients had sufficient PBMCs needed for longitudinal analysis. This study is registered on the ClinicalTrials.gov website, number NCT00739791. FINDINGS: PBMC telomerase activity expressed as natural logarithms increased from 2.00 (SD 0.44) to 2.22 (SD 0.49; p=0.031). Raw values of telomerase increased from 8.05 (SD 3.50) standard arbitrary units to 10.38 (SD 6.01) standard arbitrary units. The increases in telomerase activity were significantly associated with decreases in low-density lipoprotein (LDL) cholesterol (r=-0.36, p=0.041) and decreases in psychological distress (r=-0.35, p=0.047). INTERPRETATION: Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Given this finding and the pilot nature of this study, we report these increases in telomerase activity as a significant association rather than inferring causation. Larger randomised controlled trials are warranted to confirm the findings of this study.

In summary, the study reports that 3 months of “comprehensive lifestyle modifications” resulted in increased telomerase activity in circulating PBMCs of 24 subjects with low-risk prostate cancer. The modifications included diet (low fat, low in refined carbs, lots of fruit and vegetables), exercise (30 minutes walking per day, 6 days per week), stress management (yoga, breathing, meditation, imagery, 60 minutes per day, 6 days per week) and supplements (tofu plus soy-powdered protein, fish oil, selenium, vitamin E and vitamin C). 

Outcome measures included the standards for cardiovascular risk (blood pressure, lipid profile, body mass index (BMI), waist circumference and C-reactive protein). As one would expect with such drastic changes to diet and exercise in particular, the subjects experienced significant improvements in cardiovascular risk factors: both systolic and diastolic blood pressure decreased, as did BMI and waist circumference. Positive changes in lipid profile were also observed.

But perhaps the most critical part of the study focusses on the effect of  “psychological functioning”; subjects were assessed using the “Impact of Event Scale, a well-validated measure of distress associated with a traumatic event.” In this study, the subjects had all previously been diagnosed with low-risk prostate cancer, and so a baseline of stress was assumed to be present. At the end of the 3-month lifestyle modification, “intrusive thoughts” were reduced significantly, presumably due to a combination of the improved diet, exercise and stress reduction techniques. 

Upon detailed analysis of the data the authors report that the increased telomerase activity correlates with decreased LDL-cholesterol and decreased intrusive thoughts. Previous studies have demonstrated that both oxidised-LDL and cortisol impact on telomerase activity in vitro, providing potential mechanistic links for these observations. 

The authors stress that this pilot study reports a significant association, but that they do not infer causation.  However, the results raise another question relating to the use of telomere length in the circulating leucocytes as a proxy for other cells: does modification of telomerase activity in the leucocytes impact on their telomere length? The answer would appear to be “yes,” suggesting that “psychological functioning“ is another confounding variable when performing association studies of telomere length. My only concern is that the assessment of psychological functioning appears to be a very subjective variable; what is stressful to one person may not be to another.

Overall, the study clearly confirms the notion that a healthy diet and regular exercise is beneficial in terms of cardiovascular risk; the caveat is that if you suffer from “intrusive thoughts” as a result of worrying about your health, you may well undo all of your hard work…

AMP-activated kinase (AMPK) agonists mimic the effects of exercise, raising the possibility of a “workout pill” that could simulate the effects of vigorous activity. The applications to human health are, to mildly understate the case, significant; it sounds almost too good to be true, and it leaves one looking for the catch.

But it turns out that AMPK is activated by certain types of genotoxic stress, and contributes to UV-induced apoptosis in the skin. From Cao et al.:

AMP-activated protein kinase contributes to UV- and H2O2-induced apoptosis in human skin keratinocytes

AMP-activated protein kinase or AMPK is an evolutionarily conserved sensor of cellular energy status, activated by a variety of cellular stresses that deplete ATP. However, the possible involvement of AMPK in UV- and H2O2-induced oxidative stresses that lead to skin aging or skin cancer has not been fully studied. We demonstrated for the first time that UV and H2O2 induce AMPK activation (Thr172 phosphorylation) in cultured human skin keratinocytes. UV and H2O2 also phosphorylate LKB1, an upstream signal of AMPK, in an EGFR dependent manner. … We also observed that AMPK serves as a negative feedback signal against UV-induced mTOR (mammalian target of rapamycin) activation in a TSC2 dependent manner. Inhibiting mTOR and positively regulating p53 and p38 might contribute to AMPK’s pro-apoptotic effect on UV- or H2O2-treated cells. Furthermore, activation of AMPK also phosphorylates acetyl-CoA carboxylase or ACC, the pivotal enzyme of fatty acid synthesis, and PFK2, the key protein of glycolysis in UV-radiated cells. Collectively, we conclude that AMPK contributes to UV- and H2O2-induced apoptosis via multiple mechanisms in human skin keratinocytes and AMPK plays important roles in UV-induced signal transduction ultimately leading to skin photoaging and even skin cancer.

Note especially that last line (emphasis mine): activation of AMPK could exacerbate the pro-aging effects that UV light exerts on the skin. Judging from the peroxide results, this also applies to endogenously generated reactive oxygen species (ROS) — which one can’t avoid by simply staying out of the sun.

Before we panic and throw the exercise mimetic baby out with its gerontogenic bathwater, I’d want to see whether AMPK agonists like AICAR do in fact synergize with stresses like UV and peroxide to increase apoptotic cell death in the skin. If they do…well, I think we found that catch.

According to a recent study by Lanza et al., endurance exercise increases mitochondrial protein levels, metabolic enzyme activity, and expression of SIRT3 (a sirtuin thought to be involved in longevity assurance). At the organismal level, insulin sensitivity goes up (this is good: insulin resistance leads to type II diabetes) and gluconeogenesis goes down.

So far, so good, but hardly surprising: file under “exercise is good for you, item #68232”. The interesting bit is that the mitochondrial and other changes are very similar to the physiological consequences of calorie restriction (CR), an intervention that is known to extend lifespan in model organisms and to delay age-related disease in humans. The authors argue that exercise may promote longevity through the same pathways as CR.

This fits in nicely with recent observations connecting exercise and CR: for example, resveratrol, thought to be a CR mimetic, improves exercise tolerance in mice, consistent with the idea that exercise and CR have something in common.

The next obvious question: Do exercise mimetics also promote longevity, and if so, do they do so by the same mechanism as CR?

As a biologist of aging, one question I get asked frequently is: “What should I be doing in the meantime?” That is, in the absence of any de facto anti-aging medicine, what’s the best way to extend healthspan, and thereby improve one’s chances of being around when bona fide life extension technology becomes available? Usually, the question takes the form, “What pills should I be popping?”

My answer (after issuing the routine qualifications that I’m not an MD, a dietitian or an exercise physiologist) is as follows: Vitamins are good but megadoses are of questionable value. Ditto for “supplements”: the nutraceutical industry is poorly regulated, so you don’t necessarily know what you’re getting. Beyond that, we don’t necessarily know the efficacy or understand the mechanism of action of many of these products, which means that we can’t begin to rationally predict the adverse reactions that could result from their combination.

Kind of bleak, right? Turns out that I do have some constructive advice, however — and it’s the same advice you’ve been getting all your life: Avoid tobacco, eat a reasonable diet, and get plenty of exercise. After all, I usually jest, they’re never going to turn exercise into a pill.

That is, until they do.

Enter the era of PPARβ/δ and AMPK agonists. From Narkar et al.:

AMPK and PPARδ Agonists Are Exercise Mimetics

The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARβ/δ agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1α, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARδ pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.

Get that? Mice that performed no workout more taxing than taking their medicine were almost 50% better than controls at running — and the effects were even more dramatic when combined with actual exercise.

Assuming — standard caveat — that AMPK agonists like AICAR are efficacious in humans, the potential applications are tremendous, with potential benefits for everyone from bedridden hospital patients to astronauts at the ISS.

An interesting open question: We know that actual exercise extends lifespan, possibly via hormesis (the improvement of chronic stress tolerance in response to regular acute stress). Do the exercise-like effects of PPARβ/δ and AMPK agonists also increase longevity — and if so, does the mechanism involve hormesis? In other words, are these drugs increasing endurance by simulating the acute stress of exercise, or are they activating a response further downstream in the pathway?

We’ve recently discussed evidence that resveratrol, a compound with some documented longevity-enhancing benefits in model organisms, might act by inducing the heat shock response. Heat shock proteins have been implicated in lifespan determination: Stochastic variations in heat shock protein expression have been invoked to explain variance in longevity between genetically identical organisms, with higher HSP expression associated with longer life.

It is therefore curious to learn that exercise, also thought to have a hormetic effect (i.e., acute stress now increases chronic stress tolerance later) downregulates expression of least one heat shock protein in elderly human subjects. From Simar et al.:

Physical Activity Modulates Heat Shock Protein-72 Expression and Limits Oxidative Damage Accumulation in a Healthy Elderly Population Aged 60–90 Years

Background. Reactive oxygen species production increases during aging, whereas protective mechanisms such as heat shock proteins (HSPs) or antioxidant capacity are depressed. Physical activity has been hypothesized to provide protection against oxidative damage during aging, but results remain controversial. This study aimed to investigate the effect of different levels of physical activity during aging on Hsp72 expression and systemic oxidative stress at rest and in response to maximal exercise.

Methods. Plasma antioxidant capacity (Trolox equivalent antioxidant capacity, TEAC), thiobarbituric acid-reactive species (TBARS), advanced oxidized proteins products (AOPP), and Hsp72 expression in leukocytes were measured before and after maximal exercise testing in 32 elderly persons (aged 73.2 years), who were assigned to two different groups depending on their level of physical activity during the past 12 months (OLow = moderate to low level; OHigh = higher level).

Results. The OHigh group showed higher aerobic fitness and TEAC (both representing 120% of OLow values) as well as lower oxidative damage (50% of OLow values) and Hsp72 expression. Exercise led to a lower increase in oxidative damage in the OHigh group. Aerobic fitness was positively correlated with TEAC and negatively with lipid peroxidation (TBARS). Hsp72 expression was negatively correlated with TEAC but positively correlated with TBARS levels.

Conclusions. The key finding of this study is that, in people aged 60 to 90 years, long-term high level of physical activity preserved antioxidant capacity and limited oxidative damage accumulation. It also downregulated Hsp72 expression, an adaptation potentially resulting from lower levels of oxidative damage.

The authors’ explanation of the lowered Hsp72 levels — that lower overall oxidative damage results in an adaptive decrease in Hsp72 expression — is reasonable; Hsp72 is known to be involved in the cellular response to oxidative stress (e.g., in regulating peroxide-induced apoptosis). But what puzzles me is this: HSPs tend to be coordinately regulated, by elevated temperature or other sources of protein-folding stress. Does this finding suggest that all of the HSPs are lower in elderly patients who exercise? If so, what are the ramifications for the theory that chronically elevated HSPs are a key mechanism of resisting chronic low-level stress?