How stress might help reduce dementia and alzheimer’s.

The post today (my 80th birthday) points to experimental results relevant to my interest in not losing my marbles anytime soon. Fauzia points to work by Avezov and collaborators (open source) showing that the accumulation of aggregates of misfolded proteins in the endoplasmic reticulum of brain cells that is associated with dementia and Alzheimer's can be reversed by stressing cells with chemicals or heat, activating molecular chaperones that in turn untangle or remove protein aggregates. How much stress is just enough, but not to much, isn't clear. The abstract of the work:

Protein synthesis is supported by cellular machineries that ensure polypeptides fold to their native conformation, whilst eliminating misfolded, aggregation prone species. Protein aggregation underlies pathologies including neurodegeneration. Aggregates’ formation is antagonised by molecular chaperones, with cytoplasmic machinery resolving insoluble protein aggregates. However, it is unknown whether an analogous disaggregation system exists in the Endoplasmic Reticulum (ER) where ~30% of the proteome is synthesised. Here we show that the ER of a variety of mammalian cell types, including neurons, is endowed with the capability to resolve protein aggregates under stress. Utilising a purpose-developed protein aggregation probing system with a sub-organellar resolution, we observe steady-state aggregate accumulation in the ER. Pharmacological induction of ER stress does not augment aggregates, but rather stimulate their clearance within hours. We show that this dissagregation activity is catalysed by the stress-responsive ER molecular chaperone – BiP. This work reveals a hitherto unknow, non-redundant strand of the proteostasis-restorative ER stress response.

Older adults store too much information.

From Amer et al.:  

Highlights

Healthy aging is accompanied by declines in control of attention.

These reductions in the control of attention, result in older adults processing too much information, creating cluttered memory representations.

Cluttered representations can impair memory by interfering with the retrieval of target information, but can also provide an advantage on tasks that benefit from extensive knowledge.

Abstract

Declines in episodic memory in older adults are typically attributed to differences in encoding strategies and/or retrieval processes. These views omit a critical factor in age-related memory differences: the nature of the representations that are formed. Here, we review evidence that older adults create more cluttered (or richer) representations of events than do younger adults. These cluttered representations might include target information along with recently activated but no-longer-relevant information, prior knowledge cued by the ongoing situation, as well as irrelevant information in the current environment. Although these representations can interfere with the retrieval of target information, they can also support other memory-dependent cognitive functions.

Losing sleep with age.

Jacobson and Hoyer summarize experiments of Li et al.:

Humans spend approximately one-third of their lives asleep, but this is not distributed equally across their life span. Sleep quantity and quality decline as age advances, and insomnia and sleep fractionation are common in older people. Sleep is essential for vitality and health. At any age, chronic sleep deprivation causes a range of issues, including disrupted cognition and memory. Correspondingly, sleep complaints in older people are associated with increased risks of impaired physical and mental health and with mortality. Beyond evidence of degenerating subcortical nuclei in age-associated sleep disturbances, the underlying mechanisms remain unclear despite decades of awareness of the problem and its consequences...Li et al.report the hyperexcitability of hypocretin neurons as a core mechanism underlying sleep disruption in aged mice, explaining why sleep is punctuated by intruding wakefulness despite the loss of wake-promoting neurons.

A few clips from the Li et al. article: 

RATIONALE

We hypothesized that the decline in sleep quality could be due to malfunction of the neural circuits associated with sleep/wake control. It has been established that hypocretin/orexin (Hcrt/OX) neuronal activity is tightly associated with wakefulness and initiates and maintains the wake state. In this study, we investigated whether the intrinsic excitability of Hcrt neurons is altered, leading to a destabilized control of sleep/wake states during aging.

RESULTS

Aged mice exhibited sleep fragmentation and a significant loss of Hcrt neurons. Hcrt neurons manifested a more frequent firing pattern, driving wake bouts and disrupting sleep continuity in aged mice. Aged Hcrt neurons were capable of eliciting more prolonged wake bouts upon optogenetic stimulations. These results suggested that hyperexcitability of Hcrt neurons emerges with age. Patch clamp recording in genetically identified Hcrt neurons revealed distinct intrinsic properties between the young and aged groups. Aged Hcrt neurons were hyperexcitable with depolarized membrane potentials (RMPs) and a smaller difference between RMP and the firing threshold.

CONCLUSION

Aged mice exhibited sleep fragmentation and a significant loss of Hcrt neurons. Hcrt neurons manifested a more frequent firing pattern, driving wake bouts and disrupting sleep continuity in aged mice. Aged Hcrt neurons were capable of eliciting more prolonged wake bouts upon optogenetic stimulations. These results suggested that hyperexcitability of Hcrt neurons emerges with age. Patch clamp recording in genetically identified Hcrt neurons revealed distinct intrinsic properties between the young and aged groups. Aged Hcrt neurons were hyperexcitable with depolarized membrane potentials (RMPs) and a smaller difference between RMP and the firing threshold.

Re-energizing the aged brain

Alderton does a brief summary of work by Brakedal et al.:

Nicotinamide adenine dinucleotide (NAD) is an important cofactor in numerous metabolic reactions. NAD concentrations decline with age, which may contribute to age-associated conditions such as Parkinson’s disease. Preclinical studies show that replenishing NAD by supplementation with nicotinamide riboside (NR), a biosynthetic precursor to NAD, can promote health span and neuroprotection. Brakedal et al. performed a randomized, double-blind phase 1 clinical trial of NR supplementation in 30 patients newly diagnosed with Parkinson’s disease. They found that NR supplementation was safe and that concentrations of NAD in the brain increased in most patients receiving NR. These patients had signs of altered cerebral metabolism and mild clinical improvement, although further testing is needed with a larger cohort to confirm any clinical benefit.

Added note: I realized I had bought a jar of nicotinamide riboside some time ago ("TRU - Niagen" at an outrageious price), decided not to take it after reading about possible side effects, but relented after reading the Brakedal et al. article. I've been taking a 150 mg capsule daily for the past 10 days, half the recommended dosage. I haven't detected any noticable effects on my general energy levels.

Seven Habits That Lead to Happiness in Old Age

I want to point to this self-help article by Arthur Brooks in The Atlantic, part of his 'How to Build a Life' series. It's bottom line, derived from data in the famous Harvard Study of Adult Development begun in 1938, is that Happy-well seniors accumulate resources and habits in their Happiness 401(k)s during their younger lives by practicing the following injunctions. 

1. Don't smoke 

2. Watch your drinking 

3. Maintain a healthy body weight 

4. Prioritize physical movement in your life 

5. Practice coping mechanisms 

6 Keep learning 

 7 Cultivate stable long term relationships.

Attention and executive functions - improvements and declines with ageing.

From Verissimo et al.:

Many but not all cognitive abilities decline during ageing. Some even improve due to lifelong experience. The critical capacities of attention and executive functions have been widely posited to decline. However, these capacities are composed of multiple components, so multifaceted ageing outcomes might be expected. Indeed, prior findings suggest that whereas certain attention/executive functions clearly decline, others do not, with hints that some might even improve. We tested ageing effects on the alerting, orienting and executive (inhibitory) networks posited by Posner and Petersen’s influential theory of attention, in a cross-sectional study of a large sample (N = 702) of participants aged 58–98. Linear and nonlinear analyses revealed that whereas the efficiency of the alerting network decreased with age, orienting and executive inhibitory efficiency increased, at least until the mid-to-late 70s. Sensitivity analyses indicated that the patterns were robust. The results suggest variability in age-related changes across attention/executive functions, with some declining while others improve.

Senolytic therapies for healthy longevity

An article on increasing longevity by getting rid of senescent cells (cells that have stopped dividing and generate products that accelerate aging) has been languishing in my queue of potential posts for over a year, and I want to finally give it a mention. (This continues the thread of MindBlog posts over the years that have dealt with anti-aging supplements. You can enter 'resveratrol' in the search box in the right column of this blog to get a sample. I've reported on several self experiments, none of which ended all that well. A 2008 post on my experimenting with a resveratrol supplement generated a comment thread that has continued for many years.)

Here is the abstract of the review article by Jan M. van Deursen in Science Magazine:

The estimated “natural” life span of humans is ∼30 years, but improvements in working conditions, housing, sanitation, and medicine have extended this to ∼80 years in most developed countries. However, much of the population now experiences aging-associated tissue deterioration. Healthy aging is limited by a lack of natural selection, which favors genetic programs that confer fitness early in life to maximize reproductive output. There is no selection for whether these alterations have detrimental effects later in life. One such program is cellular senescence, whereby cells become unable to divide. Cellular senescence enhances reproductive success by blocking cancer cell proliferation, but it decreases the health of the old by littering tissues with dysfunctional senescent cells (SNCs). In mice, the selective elimination of SNCs (senolysis) extends median life span and prevents or attenuates age-associated diseases (1, 2). This has inspired the development of targeted senolytic drugs to eliminate the SNCs that drive age-associated disease in humans.

A few clips from the article:

Much of our current knowledge about the properties of SNCs is based on experiments in cultured cells, largely because SNCs in tissues and organs are difficult to identify and collect. One key characteristic of SNCs is that they are in a state of permanent cell-cycle arrest....SNCs produce a bioactive “secretome,” referred to as the senescence-associated secretory phenotype (SASP). This can disrupt normal tissue architecture and function through diverse mechanisms, including recruitment of inflammatory immune cells, remodeling of the extracellular matrix, induction of fibrosis, and inhibition of stem cell function . Paradoxically, although cellular senescence has evolved as a tumor protective program, the SASP can include factors that stimulate neoplastic cell growth, tumor angiogenesis, and metastasis, thereby promoting the development of late-life cancers. Indeed, elimination of SNCs with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.

The article proceeds to outline several different efforts to identify senolytic drug targets. It notes that:

...natural products with anticancer properties, such as quercetin and fisetin, and quercetin in combination with the pan-tyrosine kinase inhibitor dasatinib, have been reported to eliminate SNCs in vitro and in mice [M. Xu et al., Nat. Med. 24, 1246 (2018); M. J. Yousefzadeh et al., EBioMedicine 36, 18 (2018)]. Although quercetin, fisetin, and dasatinib are often referred to as senolytics, it should be noted that they each act on a myriad of pathways and mechanisms implicated in diverse biological processes. This makes it difficult to decipher how these drugs eliminate or otherwise impact SNCs and to attribute any therapeutic or detrimental effects they may have in clinical trials to senolysis.

A brief google search on these flavinoid antioxidant compounds (found in fruits and vegetables...strawberries, watercress, cilantro, etc.) finds a large number of "Life Extension" dietary supplements featuring them. There is no data on their effects on senolysis or life span in humans.

The active grandparent hypothesis

Lieberman et al. suggest that selection in humans for lifelong physical activity, including during postreproductive years to provision offspring, promoted selection for energy allocation pathways which synergistically slow senescence and reduce vulnerability to many forms of chronic diseases. Here is their abstract (motivated readers can obtain a copy of the article from me):

The proximate mechanisms by which physical activity (PA) slows senescence and decreases morbidity and mortality have been extensively documented. However, we lack an ultimate, evolutionary explanation for why lifelong PA, particularly during middle and older age, promotes health. As the growing worldwide epidemic of physical inactivity accelerates the prevalence of noncommunicable diseases among aging populations, integrating evolutionary and biomedical perspectives can foster new insights into how and why lifelong PA helps preserve health and extend lifespans. Building on previous life-history research, we assess the evidence that humans were selected not just to live several decades after they cease reproducing but also to be moderately physically active during those postreproductive years. We next review the longstanding hypothesis that PA promotes health by allocating energy away from potentially harmful overinvestments in fat storage and reproductive tissues and propose the novel hypothesis that PA also stimulates energy allocation toward repair and maintenance processes. We hypothesize that selection in humans for lifelong PA, including during postreproductive years to provision offspring, promoted selection for both energy allocation pathways which synergistically slow senescence and reduce vulnerability to many forms of chronic diseases. As a result, extended human healthspans and lifespans are both a cause and an effect of habitual PA, helping explain why lack of lifelong PA in humans can increase disease risk and reduce longevity.

New articles on exercise and the brain

Gretchen Reynolds has done two recent brief reviews:

 The Quiet Brain of the Athlete describes work showing that the brains of fit, young athletes dial down extraneous noise and attend to important sounds better than those of other young people. 

And, 

 Staying physically active may protect the aging brain. Simple activities like walking boost immune cells in the brain that may help to keep memory sharp and even ward off Alzheimer’s disease.

Caution around the fountain of youth.

Lee et al. do a review "Antiaging diets: Separating fact from fiction" in Science Magazine. The link takes you to their summary, abstract, and a nice graphic. I pass on a Box 1 from the body of the article titled "reclaiming the term 'anti-aging'":

The phrase “antiaging” is greatly abused in popular culture, often for the purpose of marketing cosmetic procedures or unproven nutritional supplements purported to slow or reverse aging. This has the unfortunate consequence of creating confusion among the general public and diminishing the impact of legitimate scientific discovery. Here, we define “antiaging” as delaying or reversing biological aging by targeting the established molecular mechanisms of aging, which have been formalized as “hallmarks” or “pillars” of aging (93, 94). Effective antiaging interventions in laboratory animals increase both median and maximum population life span and broadly delay the onset and progression of many age-related functional declines and diseases. The latter effect is often referred to as “extending health span,” which is a qualitative term referring to the period of life free from chronic disease and disability (95). Recent studies show that at least some antiaging interventions, such as the drug rapamycin, can reverse functional declines across multiple tissues in aged animals (96). On the basis of this definition, there are as yet no clinically validated antiaging interventions in humans. However, there is some evidence consistent with antiaging effects for CR and related diets in humans as well as a small number of putative geroprotective compounds, including metformin and rapamycin (97).

93. C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, G. Kroemer, The hallmarks of aging. Cell 153, 1194–1217 (2013).

94. B. K. Kennedy, S. L. Berger, A. Brunet, J. Campisi, A. M. Cuervo, E. S. Epel, C. Franceschi, G. J. Lithgow, R. I. Morimoto, J. E. Pessin, T. A. Rando, A. Richardson, E. E. Schadt, T. Wyss-Coray, F. Sierra, Geroscience: Linking aging to chronic disease. Cell 159, 709–713 (2014).

95 M. Kaeberlein, How healthy is the healthspan concept? Geroscience 40, 361–364 (2018).

96 R. Selvarani, S. Mohammed, A. Richardson, Effect of rapamycin on aging and age-related diseases-past and future. Geroscience 43, 1135–1158 (2021).

97 M. B. Lee, M. Kaeberlein, Translational Geroscience: From invertebrate models to companion animal and human interventions. Transl. Med. Aging 2, 15–29 (2018).

Metabolism modulates network synchrony in the aging brain

Wow, this work from Weistuch et al. temps me to reconsider my decision to stay away from the various mitochondrial metabolism stimulating supplements I have experimented with over the past 10-15 years (they made me a bit hyper). It has been hypothesized that declining glucose metabolism in older brains drives the loss of high-cost (integrated) functional activities (activities of the sort I'm trying to carry out at the moment in cobbling together a coherent lecture from diverse sources). From the paper's introduction:

We draw on two types of experimental evidence. First, as established using positron emission tomography, older brains show reduced glucose metabolism. Second, as established by functional MRI (fMRI), aging is associated with weakened functional connectivity (FC; i.e., reduced communication [on average] between brain regions). Combining both observations suggests that impaired glucose metabolism may underlie changes in FC. Supporting this link are studies showing disruptions similar to those seen with aging in type 2 diabetic subjects.

The Significance Statement and Abstract:  

Significance

How do brains adapt to changing resource constraints? This is particularly relevant in the aging brain, for which the ability of neurons to utilize their primary energy source, glucose, is diminished. Through experiments and modeling, we find that changes to brain activity patterns with age can be understood in terms of decreasing metabolic activity. Specifically, we find that older brains approach a critical point in our model, enabling small changes in metabolic activity to give rise to an abrupt reconfiguration of functional brain networks.

Abstract

Brain aging is associated with hypometabolism and global changes in functional connectivity. Using functional MRI (fMRI), we show that network synchrony, a collective property of brain activity, decreases with age. Applying quantitative methods from statistical physics, we provide a generative (Ising) model for these changes as a function of the average communication strength between brain regions. We find that older brains are closer to a critical point of this communication strength, in which even small changes in metabolism lead to abrupt changes in network synchrony. Finally, by experimentally modulating metabolic activity in younger adults, we show how metabolism alone—independent of other changes associated with aging—can provide a plausible candidate mechanism for marked reorganization of brain network topology.

Ageing yields improvements as well as declines across attention and executive functions

Interesting work from Verissimo et al.:

Many but not all cognitive abilities decline during ageing. Some even improve due to lifelong experience. The critical capacities of attention and executive functions have been widely posited to decline. However, these capacities are composed of multiple components, so multifaceted ageing outcomes might be expected. Indeed, prior findings suggest that whereas certain attention/executive functions clearly decline, others do not, with hints that some might even improve. We tested ageing effects on the alerting, orienting and executive (inhibitory) networks posited by Posner and Petersen’s influential theory of attention, in a cross-sectional study of a large sample (N = 702) of participants aged 58–98. Linear and nonlinear analyses revealed that whereas the efficiency of the alerting network decreased with age, orienting and executive inhibitory efficiency increased, at least until the mid-to-late 70s. Sensitivity analyses indicated that the patterns were robust. The results suggest variability in age-related changes across attention/executive functions, with some declining while others improve.

Well-being of the aging brain - from the Univ.of Wisc. Center for Healty Minds

I am a supporter of the Center for Healthy Minds  at the University of Wisconsin, Madison, which was established and is lead by one of my former colleagues, Richie Davidson, The Center has recently released the transcript  (PDF here) of an August 16 live online seminar titled "The Aging Brain: Developing Well-Being for your future," that features three researchers talking about their work on aging. Melissa Rosenkranz describes work on bi-directional mind-brain-immune pathways through which emotion and inflammation are mutually influential, Ozioma Okokwe's work is on factors influencing resilience to Alzheimer's disease, and Stacey Schaefer, who leads the neuroscience project of the midlife in the US study (MIDUS), describes work on the time course and duration of emotional response and how they relate to long term cognitive and health outcomes. At the end of the transcript graphics used in the presentations as well as sources mentioned in the lectures are given. I am finding a number of the sources quite interesting, so I paste them in below:

OPPS!  NOTE ADDED.  A READER REPORTS THE LINKS BELOW DID NOT SURVIVE MY CUT AND PASTE.  SORRY ABOUT THAT....BUT, IT YOU CLICK THE "PDF HERE" LINK ABOVE, TO GET THE TRANSCRIPT OF THE SESSION, YOU GET THE REFERENCES AT THE END AND THOSE LINKS DO WORK.    

LINKS MENTIONED:

Learn more about MIDUS here: http://midus.wisc.edu/index.php
A paper on the topic of Dementia linked to Rumination is nicely summarized here: Rumination and Worry

Linked to Increased Dementia Risk

Here's a link from the American Federation for Aging Research (AFAR) to webinars related to aging on sleep, exercise, nutrition, gaming, cognition, as well as COVID: https://www.afar.org/afar-webinars

See the long list of aging-related links on this page from the Institute on Aging:

https://aging.wisc.edu/resources/

Here’s the paper about purpose in life, loneliness, and protective health behaviors during the COVID-19 pandemic: https://academic.oup.com/gerontologist/article/61

The paper on the exercise study can be found here: https://pubmed.ncbi.nlm.nih.gov/31970... The NIAWebsite for Physical Activity can be accessed at this link: https://go4life.nia.nih.gov

Find small moments of delight to boost happiness. Check out the Joy Generator:

https://apps.npr.org/joy-generator
Visit https://hminnovations.org/meditation-app or explore Healthy Minds Innovations other well-being

tools at https://hminnovations.org/well-being-...
Here's information about the MIND diet that Dr. Schaefer referenced: (Mediterranean-DASH Intervention

for Neurodegenerative Delay diet): https://www.rush.edu/news/brain-healt...
This link has information about aging and sleep: https://www.sleepfoundation.org/aging...

Castration delays aging

I pass on this nugget by Beverly Purnell in the Editor's Choice section of this week's Science Magazine noting an interesting paper by Sugrue et al. First her summary, then the abstract of the Sugrue et al. paper.  

The summary:

As we age, our genetic material changes, not only through DNA mutation but also by epigenetic modification. Indeed, chronological age can be estimated based on analysis of DNA methylation. Male and female mammals display different average life spans, and a role for sex hormones is expected in this effect. Sugrue et al. established an epigenetic clock in sheep by examining methylated DNA in samples from blood and ears. They show that castration extends an animal's life span and feminizes the epigenome at specific androgen-regulated loci during aging.

The Abstract:

In mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age and identifying novel factors influencing the aging rate using only DNA methylation data. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), which can predict chronological age with a median absolute error of 5.1 months. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens. Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Comparable sex-specific methylation differences in MKLN1 also exist in bat skin and a range of mouse tissues that have high androgen receptor expression, indicating that it may drive androgen-dependent hypomethylation in divergent mammalian species. In characterizing these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.

Our gut microbiome pattern reflects healthy aging and survival

Interesting analysis by Wilmanski et al.:

The gut microbiome has important effects on human health, yet its importance in human ageing remains unclear. In the present study, we demonstrate that, starting in mid-to-late adulthood, gut microbiomes become increasingly unique to individuals with age. We leverage three independent cohorts comprising over 9,000 individuals and find that compositional uniqueness is strongly associated with microbially produced amino acid derivatives circulating in the bloodstream. In older age (over ~80 years), healthy individuals show continued microbial drift towards a unique compositional state, whereas this drift is absent in less healthy individuals. The identified microbiome pattern of healthy ageing is characterized by a depletion of core genera found across most humans, primarily Bacteroides. Retaining a high Bacteroides dominance into older age, or having a low gut microbiome uniqueness measure, predicts decreased survival in a 4-year follow-up. Our analysis identifies increasing compositional uniqueness of the gut microbiome as a component of healthy ageing, which is characterized by distinct microbial metabolic outputs in the blood.

Giving help to others may increase your life span.

An interesting analysis from Chen et al.: 

Significance

Social support is a key contributor to mortality risk, with effects comparable in magnitude (though opposite in direction) to smoking and obesity. Research has largely focused on either support received or support given; yet, everyday social relationships typically involve interchanges of support rather than only giving or only receiving. Using a longitudinal US national sample, this article elucidates how the balance of social support (amount of giving one does on a monthly basis relative to receiving support) relates to all-cause mortality over a 23-y follow-up period. Although correlational, one possible implication of the findings is that encouraging individuals to give support (e.g., helping others with errands) in moderation, while also being willing to accept support, may have longevity benefits.

Abstract

While numerous studies exist on the benefits of social support (both receiving and giving), little research exists on how the balance between the support that individuals regularly give versus that which they receive from others relates to physical health. In a US national sample of 6,325 adults from the National Survey of Midlife Development in the United States, participants were assessed at baseline on hours of social support given and received on a monthly basis, with all-cause mortality data collected from the National Death Index over a 23-y follow-up period. Participants who were relatively balanced in the support they gave compared to what they received had a lower risk of all-cause mortality than those who either disproportionately received support from others (e.g., received more hours of support than they gave each month) or disproportionately gave support to others (e.g., gave many more hours of support a month than they received). These findings applied to instrumental social support (e.g., help with transportation, childcare). Additionally, participants who gave a moderate amount of instrumental social support had a lower risk of all-cause mortality than those who either gave very little support or those who gave a lot of support to others. Associations were evident over and above demographic, medical, mental health, and health behavior covariates. Although results are correlational, one interpretation is that promoting a balance, in terms of the support that individuals regularly give relative to what they receive in their social relationships, may not only help to strengthen the social fabric of society but may also have potential physical health benefits.

Your blood proteins can tell you the best kind of exercise for your body

Since I am heading into my 80th year, and realizing that any further years must be regarded as a gift from nature, I'm attentive to anything that NYTimes "Phys Ed" columnist Gretchen Reynolds (who is no spring chicken) writes about exercise and aerobic fittness (both of which are strongly linked to longevity.) Most recently, she describes work by Robbins et al. that finds a correlation between the levels of different blood proteins and how individual respond to exercise.

If we all begin the same exercise routine tomorrow, some of us will become much fitter, others will get a little more in shape, and a few of us may actually lose fitness. Individual responses to exercise can vary that wildly and, until now, unpredictably. But a fascinating new study of more than 650 men and women suggests that the levels of certain proteins in our bloodstreams might foretell whether and how we will respond to various exercise regimens.

Using state-of-the-art molecular tools, the scientists began enumerating the numbers and types of thousands of proteins in each of the 654 people’s bloodstreams. Then they tabulated those figures with data about everyone’s aerobic fitness before and after their five months of exercise...The levels of 147 proteins were strongly associated with people’s baseline fitness, the researchers found. If some of those protein numbers were high and others low, the resulting molecular profiles indicated how fit someone was.

More intriguing, a separate set of 102 proteins tended to predict people’s physical responses to exercise. Higher and lower levels of these molecules — few of which overlapped with the proteins related to people’s baseline fitness — prophesied the extent to which someone’s aerobic capacity would increase, if at all, with exercise...Finally, because aerobic fitness is so strongly linked to longevity, the scientists crosschecked levels of the various fitness-related proteins in the blood of people enrolled in a separate health study that included mortality records, and found that protein signatures implying lower or greater fitness response likewise signified shorter or longer lives.

Taken as a whole, the new study’s results suggest that “molecular profiling tools might help to tailor” exercise plans. Someone whose bloodstream protein signature suggests he or she might gain little fitness from a standard, moderate walking, cycling or swimming routine, for instance, might be nudged toward higher-intensity workouts or resistance training.

Four distinct patterns of aging - what is your 'ageotype'?

An interesting piece from Lanese describs work showing how aging unfolds at different rates in different tissues:

The research team behind the study sorted 43 people into aging categories, or "ageotypes," based on biological samples collected over the course of two years. The samples included blood, inflammatory substances, microbes, genetic material, proteins and by-products of metabolic processes. By tracking how the samples changed over time, the team identified about 600 so-called markers of aging — values that predict the functional capacity of a tissue and essentially estimate its "biological age."

So far, the team has identified four distinct ageotypes: Immune, kidney, liver and metabolic. Some people fit squarely in one category, but others may meet the criteria for all four, depending on how their biological systems hold up with age.

Expanding the study will surely reveal more than four categories. One of the study participants was clearly a cardiovascular ager, whose cardiac muscle was accumulating damage at a greater rate than other parts of their body. 

This reminds me of Atul Gawande's great description of how complex systems wear down and crash:

...complex systems—power plants, say—have to survive and function despite having thousands of critical components. Engineers therefore design these machines with multiple layers of redundancy: with backup systems, and backup systems for the backup systems. The backups may not be as efficient as the first-line components, but they allow the machine to keep going even as damage accumulates...within the parameters established by our genes, that’s exactly how human beings appear to work. We have an extra kidney, an extra lung, an extra gonad, extra teeth. The DNA in our cells is frequently damaged under routine conditions, but our cells have a number of DNA repair systems. If a key gene is permanently damaged, there are usually extra copies of the gene nearby. And, if the entire cell dies, other cells can fill in.

Nonetheless, as the defects in a complex system increase, the time comes when just one more defect is enough to impair the whole, resulting in the condition known as frailty. It happens to power plants, cars, and large organizations. And it happens to us: eventually, one too many joints are damaged, one too many arteries calcify. There are no more backups. We wear down until we can’t wear down anymore.

MindBlog keeps the blood pumping

Discussion of the therapeutic effects of exercise has been one of the topic threads in MindBlog since its beginning...reporting effects of different styles of exercise on metabolic health, gene expression, markers of aging, etc. Two recent fads have been the "7-minute exercise' and ever more brief forms of intense interval exercises. Parker-Pope now points out the perfect exercises for a 78 year old fart like myself who wants to get up from his computer every hour or so to move and get the blood stirring a bit, but doesn't want to be bouncing  up and down off the floor multiple times. Trainer Chris Jordan now offers the Standing 7- inute workout, suited to bodies of any age, size or fitness level. 

The mystery of American pain - a warning for the future

Case et al. (open source) make the fascinating observation that today's elderly report less pain than those in midlife and predict that tomorrow's elderly will be sicker than today's elderly, with serious implications for healthcare. 

Significance

The elderly in the United States report less pain than those in midlife—suggesting, perhaps, that once people move into old age, their morbidity will fall. Unfortunately, assessing pain by age at one point in time masks the fact that each successive birth cohort reports more pain at any given age than the cohorts that came before it. We cannot use the experience of the elderly today to project pain prevalence of the elderly tomorrow. Today’s elderly have experienced less pain throughout their lives than those in midlife today, who will be tomorrow’s elderly. If these patterns continue, pain prevalence will continue to increase for all adults; tomorrow’s elderly will be sicker than today’s elderly, with serious implications for healthcare.

Abstract

There is an expectation that, on average, pain will increase with age, through accumulated injury, physical wear and tear, and an increasing burden of disease. Consistent with that expectation, pain rises with age into old age in other wealthy countries. However, in America today, the elderly report less pain than those in midlife. This is the mystery of American pain. Using multiple datasets and definitions of pain, we show today’s midlife Americans have had more pain throughout adulthood than did today’s elderly. Disaggregating the cross-section of ages by year of birth and completion of a bachelor’s degree, we find, for those with less education, that each successive birth cohort has a higher prevalence of pain at each age—a result not found for those with a bachelor’s degree. Thus, the gap in pain between the more and less educated has widened in each successive birth cohort. The increase seen across birth cohorts cannot be explained by changes in occupation or levels of obesity for the less educated, but fits a more general pattern seen in the ongoing erosion of working-class life for those born after 1950. If these patterns continue, pain prevalence will continue to increase for all adults; importantly, tomorrow’s elderly will be sicker than today’s elderly, with potentially serious implications for healthcare.