Probability, Aging and a Pain in the Neck....

by Brad

It seems appropriate to discuss "probability" as I wait in my seat for takeoff on my flight to Vancouver on a sunny day in San Francisco in mid-may.  First probability calculation: what’s the likelihood that it will be sunny in Vancouver, a city a thousand miles north but also on the Pacific Coast? Better than the average expectation, but probably not by much given the low correlation between weather in the Pacific Northwest with that of the Bay Area, especially in late spring and summer.

Vancouver's Chinese Garden in the Rain by Nina Zolotow

I’m not sure how many calculations of this type most people make in a day, but I tend to think this way a lot (probability calculation #2: am I an outlier in this regard, say in the 5% fringe, or is this more common that I imagine?).  The reason to bring up probability with respect to aging is that most people don’t think about probabilities and randomness in looking at their future health—or their present state for that matter—and how it might change, for better or worse.  Or more to the point, how do changes you make right now influence your health, both in the near term as well as 10 or 20 years out (probability calculation #3: I expect to live say another 25 years or so to about 85, but 90 or so seems considerably more uncertain, even with a exercise, yoga and a good diet). 

Several months ago I was aghast to read a letter to the editor in the New York Times from a woman who couldn’t understand why she unable to get pregnant in her late thirties since she had been taken care of herself, had been eating well, and practiced yoga daily.  She apparently believed that her (good) behavior would insure health and fertility through her thirities.  Probability calculation #4: what is the likelihood that a woman in her late thirities can get pregnant relatively easily, and how much is this is improved if she's in relatively good health? I suspect the answer is that the improvement is small, despite what one might expect. This is just one of thousands of puzzling, fascinating, and at times callous probabilities that govern our lives in a world governed by processes that are themselves inherently random. Try as we might to make rational decisions that we believe will influence our present and future selves in predictable ways, this is clearly not the full story. 

The birth of modern quantum physics over one hundred years ago taught us that even the most basic particles that make up our universe—electrons, protons, light, etc.—are governed by rules that are probabilistic.  Einstein’s famous lament that “God doesn’t play dice with universe” was a last stand against the onslaught of quantum weirdness and other concepts that now dominate our thinking on the physical laws of the universe.  But biology is also subject to these same probabilities, such as the underlying molecular principles of random DNA mutations in evolutionary theory.  Biological aging also has many random elements, or stochastic processes. Indeed, some theorists have resisted any notion of programmed aging or defined biological process of aging per se, and rather believe that aging is inherently driven by the sum of hundred and thousands of random events every second that ultimately contribute to the overall aging process. As Yogi Berra once said, “If you see a fork in the road, take it.”

So as I sit in my airplane seat waiting for this trip to start, I also feel the pain in my neck that hasn’t gone away after a 23-day stretch of 10-12 hour days in front of computer working on grants and papers.  Oddly, I’ve done this many times before in my academic career, but hadn’t any neck pain that didn’t take more than a day or two go away. But I’m 59 now, and this time is different.  Probability calculation #6: if I just ignore this and take some ibuprophen for a few days, will it go away on its own?  As it turned out, no such luck….  It had seemed a reasonable bet since I had done nothing I hadn’t done many time before in the last 30 years.  But of course I hadn’t factored in the "aging" component in this calculation, or the probability that this behavior was now going to come at a price.  So now I’m looking at how I can change my yoga practice to help alleviate this new and unwanted development.  Calculation #7: what’s the chance that if I spend 20-30 minutes a day in a few key poses (Downward-Facing Dog with a wall, Standing Forward Bend, a passive backbend over a rolled blanket ) that my neck pain will improve or, better yet, heal completely?  I’ll let you know in a few weeks.

And one last thing, the weather in Vancouver was beautiful when we arrived, but was followed by five days of overcast skies and intermittent rain. It was a great trip.

Aging: Terms and Theories

by Nina

I’m old enough that I’ve started to focus on doing some of the things I’ve always wanted to do but never got around to. Some are big (writing a novel!) and some are rather trivial. One of the more trivial things that I somehow never got around to was listening to my husband and fellow blogger, Professor Brad Gibson, give a talk. He’s kind of infamous for talking really fast, jumping around the room a lot, and packing his talks with lots of information and jokes. Recently I got the perfect opportunity to finally check him out in action when he gave a talk on his research on aging and age-related diseases at a scientific symposium.

And, yes, dear readers, Brad was a hyper and funny as I’d been told. And since you haven’t heard from Brad in a while, I thought I’d take the opportunity to tell you a little about what I learned from his talk. He began by defining some basic terms that I thought might be useful for you to hear as well.

Aging is the process of a system’s deterioration over time.

Aging and Age-Related Diseases is the (mostly) undefined relationship of “normal” aging and diseases known to be highly associated with aging, such as cancer, Alzheimer’s and Parkinson’s diseases, and type 2 diabetes.

Healthspan is the period during a person’s life during which they are generally healthy and free from serious or chronic illness. This is what most researchers in the aging field are focusing on increasing (as opposed to lifespan).

Compressed Morbidity is “The compression of morbidity occurs if the age at first appearance of aging manifestations and chronic disease can increase more rapidly than life expectancy. — James Fries (My translation: compressed morbidity means shortening the period of ill health that precedes a person’s death.)

Scientists understand that healthspan and compressed morbidity are important concepts because what would extending life be worth if it only meant 20 more years of serious illness and disability?

Muddy Road by Brad Gibson

Brad did make a number of jokes, but the thing that made me (and some of the audience) laugh the most was a slide about the theories of aging. He prefaced this slide by saying to his audience, as he’s said to you, that when he first came to the Buck Institute for Age Research, he assumed that scientists had a basic understanding of aging. Instead, he found that very little was currently known about aging. Then he showed a slide listing the following theories (those in bold are theories he considers the most compelling).

What is Aging?

Wear and Tear theory
Error and Repair theory
Neuroendoncrine theory
Redundant DNA theory
Genetic Control theory
Free Radical theory
Caloric Restriction/Nutrition
Cross-Linking
Waste Accumulation
Gene Mutation
Limited No. of Cell Divisions
Rate of Living
Hayflick’s Limit theory
Order to Disorder (entropy)
Death Hormone
Thymic-stimulatory theory
Mitochondrial theory
Autoimmune theory
Antagonistic Pleiotrophy
Senescence and Inflammation (SASP)Telomere Shortening
Others (Insulin, mTOR, etc.)

I don’t know about you, but I had no idea there were so many theories of aging and neither did most of the scientists in the room! (That's certainly something to keep in mind when you read about the latest anti-aging diet or supplements that are based on some theory of aging that some expert claims is fact.) Of course, while scientists don’t yet know the why of aging, we are all familiar with many of the what’s. For example, most of us understand that human beings typically lose strength and flexibility as they age (things yoga can help with, by the way). And I hope to have some posts from Shari Ser on this subject—what happens to us as we age—in the near future.

The next slide made people laugh, too, because it showed a worm looking young and fresh at 3 days and then old and wrinkly (for real) at 10 days

Stressed Mind, Stressed Cells?

by Brad

Last Friday I attended a talk by Dr. Elissa Epel called “Telomeres, telomerase and mental states: Stressed mind, stressed cells?” According to the abstract Dr. Epel supplied in advance of her seminar:

"I will discuss our UCSF research on the telomere/telomerase maintenance system and relationships to stress and other psychological states and lifestyle factors. The length of our telomeres is a predictor of health status – early disease and mortality, and may serve as an index of biological aging. We now know from 8 years of research that shorter telomere length is related to states of suffering—anxiety, depression, trauma exposure, and chronic stress. Just how much can people stabilize their telomere length through interventions such as exercise and meditation? I will discuss initial findings, suggesting that this marker appears somewhat malleable."

Dr. Epel is an Associate Professor in the Department of Psychiatry at UCSF.  She is also a co-founder of Telome Health, Inc., a relatively new company located in the Bay Area to promote the use of telomere testing as a measure of biological age and overall health status. The basic idea that Dr. Epel was promoting is that chronic stress has a negative impact on telomere length, and that stress reduction through diet, exercise, and possibly other lifestyle changes can have preserve telomere length.

You may remember I posted a piece on this subject a couple months ago that discussed telomeres, yoga and aging ("Science, Aging and Yoga"). As a recap, telomeres are sequence of nucleotides or base pairs at the ends of your DNA that serve cap off and protect DNA integrity. One of the theories of aging asserts that decreased telomere length resulting from the failure of certain cell type in the body (immune cells, stem cells, etc.) to properly renew their telomere length after rounds of cell division via the action of telomerases (enzymes that add back lost telomere DNA) can lead to cellular senescence (a terminal, not dividing state) that could play a role in aging, acting as a sort of molecular clock. The question as to whether a reduction or low telomere length is responsible human aging or diseases is still hotly debate (see NY Times article here), despite many studies showing a correlation of shortened telomeres with cancer, diabetes, osteoporosis, Alzheimer’s and other chronic diseases of aging.

Ferns by Joan Webster

Personally, I found much of the data presented by Dr. Epel not especially convincing, as it was mostly correlative, and did not provide much if any mechanistic insight. However, I was intrigued by her attempt to link the physical and mental state of “stress” that we experience daily (you know, “I’m so stressed out”) to cellular stress and damage (alteration in the physiological state of cells or tissues that can lead to damage at the molecular and cellular level). Although we are all familiar with the former use of the term “stress,” this second usage of the term “stress” is quite different, and its effects can remain hidden until it manifests into a pathological or disease state.

It is well known that emotional stress can lead to an increase in cortisol and insulin levels, as well as increases in catecholamines and inflammatory cytokines. What is less clear is how these signals are integrated at the cellular and tissue level, especially under chronic stress, some of which are not at all obvious. Most studies measuring telomere length are on carried out on immune cells present in blood, as these cells are relatively easy to collect and originate from actively dividing cells. 

The notion that chronic stress could alter telomerase activity in these proliferating immune cell types, resulting in the shortening of the telomeres and causing these cells to lose their capacity to divide (“Immunosenescence”) is certainly an interesting hypothesis. Indeed, immunosenescence is increasingly being seen as a new target for drugs and/or biologics therapy by both pharmaceutical and biotech companies. According to data presented by Dr. Epel, one group of people that apparently has a statistically significant decrease in telomere length are long-term primary caregivers, a group that is regarded as suffering from chronic stress. People with long-term depression apparently also have a similar phenotype.

And as I have discussed in an earlier post, meditation and mindfulness practices have been proposed as ways to ward off the presumed negative effects of telomere shortening. (I say presumed, because it’s still not clear to what extent shortened telomeres are by definition a bad thing, or how much shortening of telomeres is required for any negative consequences.) The science on all this is still in the very early days. It may turn out that telomere length will be one more false lead in the ongoing search for biochemical measures of biological aging. And I would be extremely wary of any company advertising to measure your telomere length or that suggests that taking supplements to increase telomere length makes any sense at all. Unfortunately, there are a growing number of companies out there they do indeed make such claims. (To their credit, Telome Health appears to be considerably more circumspect in their claims and services than most.)

I suppose what interested me the most from Dr. Epel’s seminar is that it once again reminded me of the many avenues of medical research that are converging on the notion that chronic stress is a negative factor in human health and possibly a driver in premature or accelerated aging. While the details of how this actually happens is unclear, it is interesting to consider that one of the main, if not primary, benefits of practicing yoga might be to reduce stress.  Who knows, maybe it will turn out that yoga reduces stress at both the psychological and cellular level? Too early to tell, but stay tuned….

Okay. Back to Aging.

by Brad

Okay. It’s been a while, as I’ve been busy with writing NIH grants and papers, as well as traveling. So it's time to get back to one of the central points of this blog: what is aging? It turns out this is no more clear than trying to define yoga. When I joined the Buck Institute for Research on Aging some 11 years ago, I was surprised and a little chagrined to discover how unsettled and wide open this central question of aging biology was.

This was not my original field of study, but as a chemist and structural biologist working at a major teaching university, I saw a prime opportunity to make a career shift by joining the Buck Institute and using my skill to elucidate molecular mechanisms of aging. But I had no idea how many competing theories existed on this subject, ranging from rather oblique terms like ”antagonistic pleotrophy” to more familiar ones—at least to a chemist—like “entropy” and “free radical damage.” So the other day when there was some news coverage in the New York Times of a breakthrough in aging research (see NY Times article here), I saw this as a chance to tackle this subject. The article, titled “In Body’s Shield Against Cancer, a Culprit in Aging May Lurk,” came out of the Mayo Clinic and looked at the role of senescent cells in aging (see original research here).

When cells reach a point of pathological state, either through telomere shortening or some other aberration or damage, a sequence of events are put into place that either sends these cells into a cell death pathway, or into a state of senescence, a kind of limbo non-dividing state. One reason this occurs is to avoid the formation of a cancerous cell, which the organism obviously wants to avoid. Cells that become senescent were usually thought of as sequestered cells that no longer posed a problem to the organism, but were also no longer productive. However, what this new study showed is that these senescent cells appear to have more damaging effects on neighboring cells and tissues, possibly through a secreted inflammatory signal.

Manzanita by Brad Gibson

By constructing a mutant mouse strain where the researchers could target and kill these senescent cells without harming the healthy cells, researchers found that it had a significant beneficial effect on the health of the mice, and that they lived longer. There is a lot of follow-up work to be done to confirm these studies in “normal mice” as well as in humans. In any case, the data are highly intriguing. It is also worth pointing out that when asked whether this would cure aging, the scientists were much more cautious, as they clearly understood that this is probably only one of many mechanisms that are contributing to aging. Nonetheless, it is interesting to see how inflammation comes up repeatedly as a cause or at least a driver of many age-related disease, from Alzheimer’s disease to diabetes.

One question that I would like to get back to is: what can we do as individuals to influence this process? What are the conditions that lead to cellular senescence versus cell death, for example, and what are the physiological and environmental determinants that cause as a cell to enter this critical state in the first place? If we knew the answers to these questions and as well other questions of this type, we might be able to critically examine how we can influence are own rate of aging. This question is related but separate from how we can reduce and/or cope with various age-related losses and pathologies as they emerge. Both questions will be critical to answer to reach an understanding on the practice of healthy aging.  How yoga might be a part of that practice is what we are trying to address here….