Resveratrol - protection from ravages of aging.

In mice, at least....An article in Wired Magazine points to a multi-authored study in Cell Metabolism:

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Worried sick...achieving wellness?

I always enjoy it when a good curmudgeonly antidote comes along to temper bright eyed optimism. Such a contrast is provided by Zuger's review of very different books by Snyderman and Hadler. Synderman:

With chirpy, can-do optimism...recapitulates the standard wisdom. Watch your diet, exercise, lose weight, stop smoking, be screened regularly for a variety of dire illnesses, rein in cholesterol and blood sugar, stay in touch with your doctor and be sure to check out those aches and pains pronto, just in case. So speaks the medical establishment.

While Hadler:

..who is a longtime debunker of much the establishment holds dear...reminds us...we are all going to die...holding every dire illness at bay forever is simply not an option. The real goal is to reach a venerable age — say 85 — more or less intact. And the statistics tell Dr. Hadler that ignoring most of the advice Dr. Snyderman offers is the way to do it.

An excerpt from Hadler's book:

Daily, we are offered the image of the baby-boom generation going on forever, making impossible demands on successive generations to provide pensions, health care, and community. That, too, is fatuous. However, more of us are living longer than did our parents. Clearly, the likelihood that we will enjoy life as an octogenarian has increased over the course of the twentieth century. Far less clear is whether the likelihood of becoming a nonagenarian has increased similarly. It has certainly not done so at anything like the same rate as the likelihood of being an octogenarian. The effect is so striking that it has caused many of us to wonder if there is not a fixed longevity for our species, set around eighty-five years of age. Some have likened this to a warranty: you are off warranty at eighty-five, beyond is a bonus, and well beyond is a statistical oddity. This projected demographic is consistent with current population trends. With one caveat, these hard facts seem unlikely to change. It is possible that molecular biology can alter the fixed longevity of our species. But don't hold your breath. None of us will live to see that — and maybe no one ever will.

Eighty-five (+/- a little bit) appears to be the programmed life expectancy for our species. I grant that the science is imperfect. But eighty-five is a linchpin of my personal philosophy of life. I, for one, do not care how many diseases I harbor on my eighty-fifth birthday, though I prefer not to know that they are creeping up on me. I, for one, do not care which of these diseases carries me off as long as the leaving is gentle and the legacy meaningful. Perhaps the best we can reasonably hope for is eighty-five years of life free of morbidities that overwhelm our wherewithal to cope, then to die in our sleep on our eighty-fifth birthday.

Brain Foods...

Gómez-Pinilla contributes a review article to the latest issue of Nature Reviews Neuroscience on how various dietary factors, in addition to some gut and brain hormones, increase the resistance of neurons to insults and promote mental fitness. I pass on one figure dealing with dietary omega-3 fatty acids, followed by a summary table.

The omega-3 fatty acid docosahexaenoic acid (DHA), which humans mostly attain from dietary fish, can affect synaptic function and cognitive abilities by providing plasma membrane fluidity at synaptic regions. DHA constitutes more than 30% of the total phospholipid composition of plasma membranes in the brain, and thus it is crucial for maintaining membrane integrity and, consequently, neuronal excitability and synaptic function. Dietary DHA is indispensable for maintaining membrane ionic permeability and the function of transmembrane receptors that support synaptic transmission and cognitive abilities. Omega-3 fatty acids also activate energy-generating metabolic pathways that subsequently affect molecules such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF1). IGF1 can be produced in the liver and in skeletal muscle, as well as in the brain, and so it can convey peripheral messages to the brain in the context of diet and exercise. BDNF and IGF1 acting at presynaptic and postsynaptic receptors can activate signalling systems, such as the mitogen-activated protein kinase (MAPK) and calcium/calmodulin-dependent protein kinase II (CaMKII) systems, which facilitate synaptic transmission and support long-term potentiation that is associated with learning and memory.

(Click to enlarge table.)

Young and old brains differ in encoding positive information

A number of studies have revealed a "positivity shift" with aging; whereas young adults are more likely to remember negative information than positive or neutral information, older adults may be at least as likely (or even more likely) to remember positive information compared with negative information. It has been proposed that this "positivity shift" may occur because older adults put more emphasis on emotion regulation goals than do young adults, with older adults having a greater motivation to derive emotional meaning from life and to maintain positive affect. In the service of these goals, older adults may focus their attention on things that will elicit pleasant feelings and may process positive information in a more self-referential fashion. Thus this work (slightly edited) from Kensinger and Schacter probing the issue is of interest:

Young and older adults are more likely to remember emotional information than neutral information. The authors performed a magnetic resonance imaging study examining the neural processes supporting young (ages 18–35) and older (ages 62–79) adults' successful encoding of positive, negative, and neutral objects (e.g., a sundae, a grenade, a canoe). The results revealed general preservation of the emotional memory network across the age groups. Both groups recruited the amygdala and the orbito-frontal cortex during the successful encoding of positive and negative information. Both ages also showed valence-specific recruitment: right fusiform activity was greatest during the successful encoding of negative information, whereas left prefrontal and temporal activity was greatest during the successful encoding of positive information. These valence-specific processes are consistent with behavioral evidence that negative information is processed with perceptual detail, whereas positive information is processed at a conceptual or schematic level. The only age differences in emotional memory emerged during the successful encoding of positive items: Older adults showed more activity in the medial prefrontal cortex and along the cingulate gyrus than young adults. Because these regions often are associated with self-referential processing, these results suggest that older adults' mnemonic boost for positive information may stem from an increased tendency to process this information in relation to themselves.

Figure - Regions that showed a stronger correspondence to subsequent general recognition (i.e., subsequently recognized > subsequently forgotten) for the positive items than for the neutral or negative items. Red regions showed this correspondence for both young and older adults. Green regions showed this correspondence for the older adults but not for the young adults. No regions showed this correspondence for the young adults but not the older adults, consistent with the behavioral finding that only older adults showed mnemonic enhancement for the positive items.

Update on resveratrol and aging...

Check out Nicholas Wade's article in today's NY Times. It includes mention of the report in a PLoS ONE article by Prolla and Weindruch's group here at Wisconsin that both caloric restriction and low amounts of resveratrol (near the amount of resveratrol and resveratrol-like compounds found in a 5 ounce glass of red wine) are sufficient to inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of caloric restriction in insulin mediated glucose uptake in muscle.

Brain Rules

I've been sent a review copy of "Brain Rules" by John Medina. The book, which includes a DVD, is an exuberant and entertaining hodgepodge of material thrown together out of which the author extracts "12 Principles for Surviving and Thriving at Work, Home, and School." The DVD has a perky in your face Dr. Medina leading you through the storyline. It is an enjoyable self help book, I think aimed at hooking readers less sophisticated than most of you who read this blog. A companion website offers supplemental material and references supporting each brain rule. (I find the references idiosyncratic and a bit dated). Here are the author's bottom line rules:

EXERCISE | Rule #1: Exercise boosts brain power.
SURVIVAL | Rule #2: The human brain evolved, too.
WIRING | Rule #3: Every brain is wired differently.
ATTENTION | Rule #4: We don't pay attention to boring things.
SHORT-TERM MEMORY | Rule #5: Repeat to remember.
LONG-TERM MEMORY | Rule #6: Remember to repeat.
SLEEP | Rule #7: Sleep well, think well.
STRESS | Rule #8: Stressed brains don't learn the same way.
SENSORY INTEGRATION | Rule #9: Stimulate more of the senses.
VISION | Rule #10: Vision trumps all other senses.
GENDER | Rule #11: Male and female brains are different.
EXPLORATION | Rule #12: We are powerful and natural explorers.

Older adults have a broader attention span

An article by Reistad-Long describes studies suggesting that a broader attention span may enable older adults to ultimately know more about a situation and the indirect message of what’s going on than their younger peers. For example, older people take longer to read passages that are interrupted with unexpected words or phrases, but are more likely to be successful at answering questions for which the out-of-place words might be answers. This might yield advantages in the real world, where it is not always clear what information is important, or will become important. Maybe we think of older people as wiser because they take in more information from a situation, and are able to combine it with a comparatively greater store of general knowledge.

MindBlog becomes a drop-out student at a brain enhancement site

When the folks at happy-neuron.com offered me a free log in to check out their brain enhancement/preservation exercises I said "Sure, I'll try it out and do a review." The site offers a brief discussion of the science of brain fitness is offered, and the scientific contributors have reasonable credentials. Several have associations with gerontology and aging programs, as is the case with other brain enhancements sites. The single study I was pointed to testing the effects of the happy-neuron exercises was a pilot effort carried out by Robert Bender, a geriatrics and family practice physician in Des Moines, Iowa. He did not respond to my email requesting information on the study.

Well.... to do a proper review one really has to get into it, and I tried, but simply was unable to do this. One could just pick directly from ~ 35 classic style tests (of memory, attention, language, executive function, and visual spatial skills) with a thin video game veneer, or let a "coach" present you with 20 minutes worth of exercises. I chose the "coach" option which chooses exercises for you, monitors your progress, strengths and weaknesses, etc. (It didn't tell me what my strengths and weaknesses were, but perhaps I didn't stick with it long enough for it to get back to me...) The exercises were mildly engaging and indeed left me feeling 'brain tired' after 20 minutes. I did get a bit tired of variations on the towers of Hanoi game (classic form, then basket balls in hoops, then bells in cathedral towers, etc.) I found the 'exit' or 'next' buttons sometimes blanked out or froze the browser window.

I found it difficult to get hooked on the system in a daily basis (I came along before the video game revolution on which my kids were raised). The exercises soon took on an "eat your spinach" aspect. I suspect my motivation might have been greater to pursue them if had been accumulating more striking evidence of my own impending cognitive decline.

I did find it very interesting to pursue the exercises to the point of brain fatigue, which my brain was clearly saying "enough of this, dammit, I'm tired." However, I have not found exercise to the point of fatigue useful or relevant in the daily gym routine to which I am addicted (varying combinations of running, swimming, weights at the Univ. of Wisconsin gym). I feel it would take a similar sort of addiction process to bind me to the routine performance of games like these, and I did not get reinforcement from the "coach" that might have nudged me in that direction ("Hey, you're doing great on executive function and rotating visual images, but your short term memory sucks...")

I may continue to putter with this as well as other brain exercise sites, and if lightning strikes and I get enthusiastic, I'll report back to you.

An aging guide...

Check out the guided tour provided by the NY Times Well.

Brain exercises

A few moments with google, using search items like "brain exercises" will immediately bring you to a large number of web sites that offer to improve your mental function, combat the decay of mental performance with aging, etc. Some of these have appeared since my previous posting which listed several. A recent NYTimes article (from which the graphic on the left is taken) points to a number of these sites and offers an interesting discussion.

I have held back from taking the plunge into brain exercises, partly because I'm afraid of what I might find find out about how far gone I already am, and partly because some which appear to be most thoroughly researched and academically respectable want your money. But, now happy-neuron.com has offered me a free login to try out their regime, and so I have taken the bait. I will be offering my opinion of this site after immersing in their 20 min exercise sessions for a few weeks, and if I have the stamina or remaining self-esteem (and get offered a free login), will review some of the other sites in subsequent posts.

The Posterior–Anterior Shift in Aging

Here is some more interesting information on brain changes with aging (material I almost don't want to know about, knowing that I'm surely well along with the 'compensations for neural decline' being described.... ):

Older adults reallocate neural resources, increasing activity in prefrontal cortex to perform cognitive tasks, presumably to compensate for declining neural processing in posterior brain regions. Davis et al. show: 1). that this reflects the effects of aging rather than differences in task difficulty (i.e. not due to the same cognitive tasks tending to be more demanding for older adults than for younger adults); 2). that the shift in fact reflects compensation (the age-related increase in PFC activation is positively correlated with cognitive performance and negatively correlated with the age-related decrease in occipitotemporal activity.); and 3). that the deactivation of the midline "default network" associated with conscious rest processes, which must be suppressed for successful cognitive performance, is reduced in posterior midline cortex but increased in medial frontal cortex.

The experiments were performed on 12 younger (mean age = 22.2 years) and 12 older adults (mean age = 69.2 years), presumably referenced by the Y and O prefixes in this figure from the paper (I'm not clear from the text on what distinguishes YM and YP, but I think they refer to the two different tasks, episodic retrieval and visual discrimination).

Figure (click to enlarge) - The posterio-anterior shift pattern for activations: across 2 different tasks and 2 levels of confidence, the occipital cortex showed greater activity in younger than in older adults A, whereas PFC showed the opposite pattern (B). The PASA pattern for deactivations: across 2 different tasks and 2 levels of confidence, posterior midline cortex (precuneus, C) showed greater deactivations in younger than older adults, whereas the anterior midline cortex (medial PFC, D) showed the opposite pattern. Notes: Activation bars represent effect size for each modeled effect, and error bars represent standard error for peak activity across participants.

A longevity-o-meter

Check out the "Vitality Compass" at the Blue Zones Community website. The results of a 2-3 minute quiz are based on a complex, 106-page algorithm developed by Dr. Robert Kane, a physician and a professor at the University of Minnesota School of Public Health. Here is my result (I'm 66 years old). Blue zone years refer to the number of years one has gained or lost given one's current behaviors.:

Brain network disruption during aging.

Most work on brain changes with aging has focused on individual regions, especially those in the frontal lobe, which may shrink or lose activity even in the absence of disease. Andrews-Hanna et al. offer an important paper showing how long range interactions between brain regions are compromised with aging. The work looked at neural activity during a task in two large-scale networks that span the brain: the default network, used when we’re worrying, thinking of the past and future, or imagining people in our lives; and the attention network, used when we’re focusing on a specific task, such as word processing or math problems. The brain regions making up these systems were in sync in young people, but much less so, or not at all, in people over 60.

Figure - the younger brain, below, shows more synchronized activity than the older brain, above.

Mine is longer than yours....

The last game of the baby boomers: Who wins is not who has the most toys, but who lives longest. Check out this great New Yorker article by Michael Kinsley. And, by the way, you might refer back to my May 2, 2007 post on Gawande's excellent article on aging.

The Amazing Aging Brain

Check out this interesting site, illustrating how the brain changes on aging.

A test for Alzheimer's risk

A news piece by Jennifer Couzin in the Feb. 22 Science notes that starting in about a month, for ~$400, you can send a saliva sample to Smart Genetics in Philadelphia for their "Alzheimer's Mirror" test that determines whether you have a variant of the APOE gene that indicates a risk of Alzheimer's that's 3 to 15 times higher than normal. The company plans plan to screen out those who seem emotionally unstable and provide a genetic counseling session by telephone before giving out APOE results.

Not surprisingly many physicians and researchers are expressing reservations about making this gene test widely available. What are the mental health consequences of being told you may get a disease that's neither preventable nor treatable and is invariably fatal? (It's the only genetic information that James Watson, the DNA discoverer who recently had his entire genome sequenced, kept secret.) Would it turn out that people who had this information were more likely experience depression?

An officer at Smart Genetics argues that knowing one is at higher risk might trigger practical responses, including regular memory screenings or making certain financial decisions such as buying long-term care insurance.

The Fires of Aging

Donna Holmes offers an interesting review with the title of this post, of Caleb Finch's new book "The Biology of Human Longevity." Here are a few edited clips from that review:

Metabolically speaking, we're all on fire. Current thinking in the biology of aging suggests that the normal processes cells use to burn fuel, providing energy for life, indirectly lead to much of the disease and disability that characterize aging in humans and other animals. Chemically unstable by-products of cellular oxidation--especially free oxygen radicals--can initiate the deterioration of cell membranes and macromolecules. As small "hits" causing cellular injury accumulate, the results can range from uncorrected mutations and cancers to forms of tissue damage leading to vascular pathology and Alzheimer's disease.

Oxidative damage remains a central player in the drama Fitch unfolds, but now it shares the stage with several lesser-known, equally important accomplices: inflammation, damage during development, and the hazards of overnutrition.

Finch proposes that increases in brain size and the human life span over the past million years occurred in concert with changing nutritional priorities, slower developmental rates, and a tolerance for inflammation in "dirty, invasive, and stingy" prehistoric environments. The integration of more meat into the human diet, he argues, provided protein needed for larger brains but involved new physiological and genetic trade-offs between fitness and liability for long-term damage. This scenario provides a satisfying rationale for why variants of some genes for metabolizing animal fat that are linked to a human predilection for atherosclerosis, some cancers, and the amyloid plaques characteristic of Alzheimer's disease (such as those of the ApoE gene family) are not shared by our closest primate relatives.

Life expectancy increases

Taken from an article by Kirkwood on a systems biology approach to longevity...


The graph shows the life expectancy in the then longest-living country. During the nineteenth and early twentieth centuries, the increase was driven mainly by improvements in sanitation, housing and education, causing a steady decline in early and mid-life mortality, which was chiefly due to infections. This trend continued with the development of vaccines and then antibiotics. By the latter half of the twentieth century, there was little room for further reduction in early and mid-life mortality. The continuing increase is due almost entirely to a new phenomenon: the decline in late-life mortality.

Your brain is shrinking sooner than you thought...

Here is a chilling little item from Pieperhoff et al., who examined MRI images of the brains of 51 healthy male subjects from 18 to 51 years old. They found age-related volume declines in circumscribed brain regions: the sensorimotor system, encompassing the cerebellum, thalamus, somatosensory and motor cortices, and the prefrontal system, encompassing the anterior cingulate as well as the lateral and basomedial frontal cortices. Regions belonging to other functional systems, such as the auditory system or the visual system, did not show such age–volume relationships.

Horizontal sections of the reference brain with statistical maps, showing the t values of age-related volume decline and increase. t values were calculated by a two-sided t test for a linear regression in the voxels of the LVR maps, depending on age.

Staying a Step Ahead of Aging

Being a person who exercises daily at moderate levels, the New York Times article with the title of this post was not a welcome read. It argues that blowing yourself away every few days is a better deal - i.e., that exercising intensely is more important than exercising often. I've always been suspicious of the 'no pain, no gain' school of exercise, thinking that while it might work for younger folks, it might not be taking enough account of potential long term inflammatory responses in people over 50.