Age related cognitive decline and the gut microbiome

Haridy summarizes experiments by D'Amato et al. showing that fecal transplants from old mice to young mice result in the younger animals displaying learning and memory impairments. It would be interesting to expand this work to check whether transferring fecal transplants from young to older mice improved their learning and memory, as is the case with blood transfers from younger to older mice. Here are the background and results sections of the open source research paper. 

Background

The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems; however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients altered the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process and related functions.

Results

Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. We report that FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, the detrimental effect of FMT from aged donors on the CNS was confirmed by the observation that microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype; on the contrary, gut permeability and levels of systemic and local (hippocampus) cytokines were not affected.

Bodybuilding supplement promotes healthy aging and extends life span

...at least in mice. I pass on clips from this piece by by Jocelyn Kaiser:

A dietary supplement bodybuilders use to bulk up may have a more sweeping health benefit: Staving off the ravages of old age. Mice given the substance—alpha-ketoglutarate (AKG)—were healthier as they aged, and females lived longer than mice not on the supplement.

AKG is part of the metabolic cycle that our cells use to make energy from food...The molecule grabbed attention as a possible antiaging treatment in 2014, when researchers reported AKG could extend life span by more than 50% in tiny Caenorhabditis elegans worms... In the new study, Gordon Lithgow and Brian Kennedy of the Buck Institute for Research on Aging and colleagues turned to mammals. They gave groups of 18-month-old mice (about age 55 in human years) the equivalent of 2% of their daily chow as AKG until they died, or for up to 21 months. AKG levels in blood gradually drop with age, and the scientists’ aim was to restore levels to those seen in young animals.

Some differences jumped out within a few months: “They looked much blacker, shinier, and younger” than control mice, says Azar Asadi Shahmirzadi, a postdoc at the Buck Institute who did the experiments as a graduate student. In addition, the AKG-fed mice scored an average of more than 40% better on tests of “frailty,” as measured by 31 physiological attributes including hair color, hearing, walking gait, and grip strength. And female mice lived a median of 8% to 20% longer after AKG treatment began than control mice, the group reports today in Cell Metabolism...The AKG-eating mice did not perform better on tests of heart function or treadmill endurance, however, and the tests did not include cognitive performance.

Probing the mechanism for these improvements, the researchers found that female mice receiving AKG produced higher levels of a molecule that tamps down on inflammation. Chronic inflammation can spur many diseases of aging such as cancer, heart disease, arthritis, and dementia.

Kennedy, now also at the National University of Singapore, plans to test AKG in human volunteers soon. Looking at a group of people between the ages of 45 and 65, his group will see whether the molecule improves aging-related biomarkers such as inflammation, arterial hardening, and a type of chemical signature on DNA associated with aging. The company Ponce de Leon Health, where Kennedy serves as chief scientific officer (and Gordon and other paper authors have stock), is running a similar study at Indiana University.

Ponce de Leon Health already sells a formulation of AKG called Rejuvant that it says can “slow the aging process.” Kennedy defends these claims. “We are upfront about the data that we have and do not yet have on the website,” he says. And Brown-Borg notes the Buck Institute team isn’t the first group of aging-focused researchers to start a company to develop an antiaging treatment, an idea she hopes will eventually pan out in clinical trials

The active grandparent hypothesis - an evolutionary explanation of why and how exercise delays senescence and death.

I recommend that you read an interesting article by Daniel Lieberman in the current issue of Harvard Magazine. Here are a few clips:

The evidence that hunter-gatherers stay physically active for several decades after they stop having children is fundamental for understanding the nature of human aging. Most especially, our uniquely cooperative system of intergenerational cooperation and food-sharing postpones Medawar’s grim shadow. Instead of becoming obsolete, middle-aged and elderly hunter-gatherers bolster their reproductive success by provisioning children and grandchildren, doing childcare, processing food, passing on expertise, and otherwise helping younger generations. Once this novel cooperative strategy—the essence of the hunting and gathering way of life—started to emerge during the Stone Age, natural selection had the chance to select for longevity. According to this theory, hard-working and helpful grandparents who looked out for others and who were blessed with genes that favored a long life had more children and grandchildren, thus passing on those genes. Over time, humans were evidently selected to live longer to be generous, useful grandparents. One version of this idea is known as the Grandmother Hypothesis in recognition of the evidence that grandmothers play especially important roles.

In order to elucidate the links between exercise and aging, I propose a corollary to the Grandmother Hypothesis, which I call the Active Grandparent Hypothesis. According to this idea, human longevity was not only selected for but was also made possible by having to work hard during old age to help as many children, grandchildren, and other younger relatives as possible survive and thrive. That is, while there may have been selection for genes (as yet unidentified) that help humans live past the age of 50, there was also selection for genes that repair and maintain our bodies when we are physically active. As a result, many of the mechanisms that slow aging and extend life are turned on by physical activity, especially as we get older. Human health and longevity are thus extended both by and for physical activity.

While exercise restores most structures (what biologists term homeostasis), in some cases it may create stability by making things even better than before (allostasis). For example, demanding physical activities can increase the strength of bones and muscles, increase cells’ abilities to uptake glucose from the blood, and both augment and replace mitochondria in muscles. In addition, repair mechanisms sometimes overshoot the damage induced by exercise, leading to a net benefit. It’s like scrubbing the kitchen floor so well after a spill that the whole floor ends up being cleaner. All in all, the modest physiological stresses caused by exercise trigger a reparative response yielding a general benefit, a phenomenon sometimes known as hormesis.

Changes as MindBlog's autonomic nervous system ages 11 years

Actually, the original title of this MindBlog post on June 11, 2013 was "Changes as an autonomic nervous system ages 11 years - The "Wild Divine" is a bit less wild." - I'm reviewing old MindBlog posts (very slowly, as it turns out) and in most cases resisting the temptation to re-post even ones I thinks are quite interesting. This personal one really hit me, owever, so I pass it on, wondering how much further the noted decrease in my ability to regulate autonomic nervous system parameters has progressed by age 78:

Just after I retired from being a Univ. of Wisconsin department chair in 2001 I bought a set of finger sensors that fit on one's three middle fingers to report skin conductance and heartbeat to a PC or MAC via an A/D converter. These were part of a package with several CDs that installed a new age game on the computer that lead you through a rich environment of classical greek temples and waterfalls, attended by soothing music, that presented tasks in which you dinked with your own heart rate variability and sympathetic (arousing)/parasympathetic (calming) balance, going alternatively through periods of calm and arousal. I thought it was a hoot, and took the time to go through the "Journey to Wild Divine: passage" and "Journey to Wild Divine: Wisdom Quest."

Some of the current incarnations of these programs have moved to web browsers. Over the years a number of heavy weight new age gurus have signed on with their wares - Deepak Chopra, Dean Ornish, and Andrew Weil (Weil was in my Harvard graduating class...I'm tempted, but I won't burden you with my jaded opinion of this class of entrepreneurs, particularly Mr. Chopra.)

The main point of this post is note my experience on pulling out the finger sensors after 11 years trying the same exercises in their new presentation. What's the difference when this 71 year old tries the same manipulations of calm and arousal that the 60 year old played with with 11 years earlier? In a nutshell, I have less command over heart rate variability, which is lower, as the swings between calm and arousal have less amplitude.

And indeed, this fits with the literature on changes in the autonomic nervous system that occur on aging. If you simply do a google search for "autonomic nervous system and aging" numerous references appear that document how healthy aging is associated with lowered heart rate variability, elevated basal sympathetic nervous activity, and reduction of overall autonomic reactivity of sympathetic and parasympathetic nervous systems. Here is a very recent review, from which I pass on one figure:

Schematic of proposed features associated with the imbalance in the autonomic nervous system during aging. During aging there is a shift in the balance of the autonomic nervous system (ANS) towards the sympathetic nervous system (SNS). This may be influenced by circulating or local brain levels of angiotensin (Ang) II and leptin. The lower activity of the parasympathetic nervous system (PSNS) is proposed to result at least in part from an age-related decline in Angiotensin-(1–7). Lower Angiotensin-(1–7) and higher Ang II or leptin in the brain medulla would predispose to a decline in baroreceptor reflex sensitivity (BRS) for control of heart rate and heart rate variability (HRV), both of which are associated with aging. Moreover, impairments in BRS and HRV can contribute to target organ damage, including metabolic dysfunction, with or without an increase in blood pressure. 

If you're inclined, like Mr. Dylan Thomas, to not "go gently into that good night" you can find numerous sources (example here) on slowing these aging changes, usually by some sort of physical movement or stimulation.

Inflammaging and COVID-19

I pass on the first paragraph from a Science Perspectives article by Akbar and Gilroy, and suggest that you have a look at the whole article.

Aging is associated with increased morbidity arising from a range of tissue dysfunctions. A common denominator of age-associated frailty is increased baseline inflammation, called inflammaging, that is present in older individuals. Recent studies have shown that the presence of excessive inflammation can inhibit immunity in both animals and humans and that this can be prevented by blocking inflammatory processes. This finding has important implications for the immunity of older individuals who are infected with pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that induce overwhelming inflammation, which can be fatal, particularly in older people. Reducing inflammation may be a therapeutic strategy for enhancing immunity in older people.

Mindblog does another anti-aging experiment.

This is a repeat of a MindBlog post done Oct. 10, 2010, encountered during an on-and-off review I'm doing of old blog posts. Five comments on the post can be seen by clicking the link to the original post. I'm halfway tempted, it now being roughly 10 years later, to repeat the experiment.

I find myself both spooked and sparked by my second foray into anti-aging chemistry (the first being the unsuccessful resveratrol dalliance described in a previous post.) A colleague pointed me to work of Bruce Ames and collaborators (also here) which has led to the marketing by Juvenon of a dietary supplement containing Acetyl L-carnitine, alpha-lipoic acid, and the B-vitamin biotin. Experiments on rats show that these compounds reverse the age related decay in energy metabolism in mitochondria and also inhibit oxidative damage to mitochondrial lipids. So... the idea is that these supplements might energize and juice you up a bit.  The Juvenon supplement contains (per day) 600 mcg biotin, 2000 mg of acetyl-L-carnitine, and 800 mg of alpha lipoic acid.  I though $40 was a bit steep for a 30 day supply, and so I bought the equivalent supplements from Swanson Health Products for significantly less money.  I decided to take 600 mg of the carnitine/day, 1000 mg/day of the alpha lipoic acid,  and 1000 mcg/day of biotin,  half at breakfast, half at lunch (by the way, this is slightly less than 1% of the levels used in the rat experiments.) From the homework I have done so far, the levels of these supplements being taken have no documented adverse side effects.

The results?  Well.... sufficiently dramatic that I really can't credit that it is all a placebo effect,  because I go into any such experiment as an unbeliever... The first several days I felt a phase change, a  step up in energy level and kinetic energy that made me like a 20-something again, a bit incredulous, as in "whoa.. where did this come from."  With both brain and body feeling like an automobile engine running at 2,000 r.p.m. even when it was not in gear,  I cut the levels of the supplements by a half after three days.   After another three days of energy I didn't know what to do with,  generating what felt like excess brain and body "noise,"  I stopped the supplement,  deciding that my normal fairly robust daily routines (including daily gym work or swimming, running, or weights) apparently had all the energy they needed.

Any experiences or references from blog readers would be appreciated.

Benefits of exercise on aging brain obtained without exercise - by plasma transfer.

There is a large literature on beneficial effects of exercise on brain health in agings adults such as improving memory and cognition. Mouse experiments by Horowitz et al. raise the possibility that affluent human couch potatoes might be able to obtain these benefits by receiving injections of plasma (blood without its cellular components) from people who have exercised. They transferred plasma from regularly exercising adult or aged mice to aged sedentary mice. This increased the formation of new hippocampal neurons, increased the concentrations of neurotrophic factors, and improved cognition in behavioral tests of the sedentary mice. Their abstract:

Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)–specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.

Lower socioeconomic status and the acceleration of aging.

An analysis from Steptoe and Zaninotto, who show that lower wealth correlates with accelerated aging independently of the presence of health conditions:

Significance

Lower socioeconomic status (SES) is a determinant of many of the health problems that emerge at older ages. The extent to which lower SES is associated with faster decline in age-related functions and phenotypes independently of health conditions is less clear. This study demonstrates that lower SES (defined by wealth) is related to accelerated decline over 6 to 8 y in 16 outcomes from physical, sensory, physiological, cognitive, emotional, and social domains, independently of diagnosed health conditions, self-rated health, education, and other factors. It provides evidence for the pervasive role of social circumstances on core aging processes and suggests that less affluent sectors of society age more rapidly than more privileged groups.

Abstract

Aging involves decline in a range of functional abilities and phenotypes, many of which are also associated with socioeconomic status (SES). Here we assessed whether lower SES is a determinant of the rate of decline over 8 y in six domains—physical capability, sensory function, physiological function, cognitive performance, emotional well-being, and social function—in a sample of 5,018 men and women aged 64.44 (SD 8.49) y on average at baseline. Wealth was used as the marker of SES, and all analyses controlled for age, gender, ethnicity, educational attainment, and long-term health conditions. Lower SES was associated with greater adverse changes in physical capability (grip strength, gait speed, and physical activity), sensory function (sight impairment), physiological function (plasma fibrinogen concentration and lung function), cognitive performance (memory, executive function, and processing speed), emotional well-being (enjoyment of life and depressive symptoms), and social function (organizational membership, number of close friends, volunteering, and cultural engagement). Effects were maintained when controlling statistically for other factors such as smoking, marital/partnership status, and self-rated health and were also present when analyses were limited to participants aged ≤75 y. We conclude that lower SES is related to accelerated aging across a broad range of functional abilities and phenotypes independently of the presence of health conditions and that social circumstances impinge on multiple aspects of aging.

Brain correlates of the muting of our emotions as we age.

 (This is a re-post of the MindBlog post of Oct. 1, 2008, as relevant today as then.)

My boyfriend in the early 19980’s was a pharmacy graduate student whose t-shirt read “Drugs are my life.” If I were to wear such a t-shirt now it would read “Hormones and neurotransmitters are my life.” I increasingly feel that all this verbal stuff we do - chattering in person or in the electronic ether, writing blogs, etc. - is a superficial veneer, noise on top of what is really running the show, which is the waxing and waning of hormones and neurotransmitters directed by an “it”, a martian inside us utterly running its own show. These compounds regulate our assertiveness versus passivity , our trust versus mistrust, our anxiety versus calm, our pleasure during antipication and reward. (They function, respectively, in neural systems that use testosterone, oxytocin, adrenaline, and dopamine.). The swings in these systems become less dramatic as we 'mellow' with aging.

Dreher et al. have published an interesting bit of work that deals specifically with the muting of the intensity of the pleasures we feel during anticipation and reward, in their article on “Age-related changes in midbrain dopaminergic regulation of the human reward system.” Their data show what is going on as we experience less excitement at opening a present when we are 60 than when we are 10 years old. There are changes in the brain's production of dopamine, which plays a central role in our reward system, as well as in which parts of the brain respond to it, and by how much they respond. (a recent brief article on dopamine and the reward system of the brain is here.) Here is their abstract, followed by a figure from the paper.

The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging. Significant losses over a normal lifespan have been reported for dopamine receptors and transporters, but very little is known about the neurofunctional consequences of this age-related dopaminergic decline. In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans, although indirect evidence from pharmacological and clinical studies also supports such an association, there has been no direct demonstration of a link between midbrain dopamine and reward-related neural response. Moreover, there are no in vivo data for alterations in this relationship in older humans. Here, by using 6-[18F]FluoroDOPA (FDOPA) positron emission tomography (PET) and event-related 3T functional magnetic resonance imaging (fMRI) in the same subjects, we directly demonstrate a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans, show that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship (from a positive to a negative correlation) between midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide system-level information about alteration of a key neural circuit in healthy aging. Taken together, our findings provide an important characterization of the interactions between midbrain dopamine function and the reward system in healthy young humans and older subjects, and identify the changes in this regulatory circuit that accompany aging.


Legend (click on figure to enlarge). Statistical t maps of the within-groups effects in the different phases of the reward paradigm. (A) (Left) Main effect of anticipating reward in young subjects during the delay period, showing activation in the left intraparietal cortex, ventral striatum, caudate nucleus, and anterior cingulate cortex. (Right) Main effect of anticipating reward in older subjects during the delay period, showing activation in the left intraparietal cortex only. The glass brain and the coronal slice indicate that no ventral striatum activity was observed in older subjects. (B) (Left) Main effect of reward receipt in young subjects at the time of the rewarded outcome showing activation in a large bilateral prefronto-parietal network. (Right) Main effect of reward receipt in older subjects at the time of the rewarded outcome showing bilateral prefronto-parietal activation.

The molecular choreography of acute exercise

Reynolds points to work of Contrepois et al, who had 36 volunteers, age range 40-75, complete a standard treadmill endurance test, running at an increasing intensity until exhaustion, usually after about nine or 10 minutes of exercise. Blood was drawn before, immediately after, and again 15, 30 and 60 minutes later. The measured the levels of 17,662 different molecules. Of these, 9,815 — or more than half — changed after exercise, compared to their levels before the workout.

Highlights

• Time-series analysis reveals an orchestrated molecular choreography of exercise

• Multi-level omic associations identify key biological processes of peak VO 2

• Prediction models highlight resting blood biomarkers of fitness

• Exercise omics provides insights into the pathophysiology of insulin resistance

Summary

Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.

People aged 95 and older show stronger brain connectivity

Jiyang et al. have used resting-state functional MRI to compare 57 individuals aged 95-103 years old with 66 cognitively unimpaired younger participants aged 76-79. The centenarians showed more synchronized activation of left and right fronto-parietal control networks. Their abstract:

Highlights

We studied functional connectivity (FC) in near-centenarians and centenarians (nCC).

NCC showed stronger FC between bilateral frontoparietal control network (FPCN).

The stronger bilateral FPCN FC was linked to better visuospatial ability in nCC.

Abstract

Centenarians without dementia can be considered as a model of successful ageing and resistance against age-related cognitive decline. Is there something special about their brain functional connectivity that helps them preserve cognitive function into the 11th decade of life? In a cohort of 57 dementia-free near-centenarians and centenarians (95–103 years old) and 66 cognitively unimpaired younger participants (76–79 years old), we aimed to investigate brain functional characteristics in the extreme age range using resting-state functional MRI. Using group-level independent component analysis and dual regression, results showed group differences in the functional connectivity of seven group-level independent component (IC) templates, after accounting for sex, education years, and grey matter volume, and correcting for multiple testing at family-wise error rate of 0.05. After Bonferroni correction for testing 30 IC templates, near-centenarians and centenarians showed stronger functional connectivity between right frontoparietal control network (FPCN) and left inferior frontal gyrus (Bonferroni-corrected p ​= ​0.024), a core region of the left FPCN. The investigation of between-IC functional connectivity confirmed the voxel-wise result by showing stronger functional connectivity between bilateral FPCNs in near-centenarians and centenarians compared to young-old controls. In addition, near-centenarians and centenarians had weaker functional connectivity between default mode network and fronto-temporo-parietal network compared to young-old controls. In near-centenarians and centenarians, stronger functional connectivity between bilateral FPCNs was associated with better cognitive performance in the visuospatial domain. The current study highlights the key role of bilateral FPCN connectivity in the reserve capacity against age-related cognitive decline.

An "Apostle's Creed" for the humanistic scientific materialist?

(Note: I have begun to slowly go though the posts on MindBlog, which began in Feb. of 2006, over 14 years ago.  Here I repeat the post that appeared on March 14, 2006.  I could have written it yesterday, without changing a word.)

The classical Christian apostle's creed, over 1600 years old and formulated soon after the writing of the New Testament, is a series of "I believe....." statements. Without thinking too much about it, I've decided to quickly write down a few sentences to suggest the very different creed that I follow. Here they are:

I believe the most fundamental content of our minds to be the sensed physical breathing and moving body, a quiet awareness that underlies our surface waves of emotions and thoughts.

I believe that this awareness can begin to experience a larger process, closer to the machinery that is generating a self, a process that observes rather than being completely defined by the current narrative "I" chatter of who-I-am or what-it-is-I-do.

I believe that this awareness can expand to feel its part in a a drama of evolving life on this planet and an evolving universe - a theater much more universal than conventional cultural or religious myths.

I believe that this awareness can enhance the depth, sanity, and sensed completion of each moment. It provides a sense of wholeness and sufficiency from which actions rise. It makes contact with other humans more sane and whole.

Ketogenic diet enhances brain network stability, a biomarker of aging

Mujica-Parodi et al. make observations suggesting that diets that changes the predominant dietary fuel from glucose (from carbohydrates) to ketones (from fats) increase available energy and enhance functional communication between brain regions, thus showing potential in protecting the aging brain. 

Significance

To better understand how diet influences brain aging, we focus here on the presymptomatic period during which prevention may be most effective. Large-scale life span neuroimaging datasets show functional communication between brain regions destabilizes with age, typically starting in the late 40s, and that destabilization correlates with poorer cognition and accelerates with insulin resistance. Targeted experiments show that this biomarker for brain aging is reliably modulated with consumption of different fuel sources: Glucose decreases, and ketones increase the stability of brain networks. This effect replicated across both changes to total diet as well as fuel-specific calorie-matched bolus, producing changes in overall brain activity that suggest that network “switching” may reflect the brain’s adaptive response to conserve energy under resource constraint.

Abstract

Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n = 292, ages 20 to 85 y; n = 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (d-β-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

Arthur Brooks on "The Hero's Journey" and retirement

In the most recent installment of Arthur Brooks’ biweekly column in The Atlantic, which I suggest that you read, he talks about the classical hero's journey in literature, described by Carl Jung and Joseph Campbell as a lens through which many people see their lives:

It’s a nice narrative, especially if you’ve worked hard and done pretty well in life. The problem is the real-life ending, after the triumphant return...The hero’s journey is great when you’re in the middle of it. The trouble comes when your strengths start to wane, because now you’re off script...Joseph Campbell...notes that...“The first problem of the returning hero is to accept as real, after an experience of the soul-satisfying vision of fulfillment, the passing joys and sorrows, banalities and noisy obscenities of life.” In other words, the end of the true hero’s journey is coming home and finding a battle to be waged not with an external enemy, but with one’s own demons...your skills will decline, and life’s problems will intrude. If you try to hang on to glory, or lash out when it fades, it will squander your victories and mark an unhappy end to your journey.

Plan to spend the last part of your life serving others, loving your family and friends, and being a good example to those still in the first three stages of their own hero’s journey. Happiness in retirement depends on your choice of narrative.

Young blood plasma reverses the epigenetic aging clock.

Perhaps the best molecular biomarker of aging at present is the epigenetic clock, developed by Horvath and others, based on measurements of DNA methylation. Josh Mitteldorf points to experiments by Horvath et al. recently posted in a preprint (not yet reviewed) in bioRxiv. noting how methylation patterns characteristic of aging can be reversed.

...plasma treatment of the old rats [109 weeks] reduced the epigenetic ages of blood, liver and heart by a very large and significant margin, to levels that are comparable with the young rats [30 weeks]….According to the final version of the epigenetic clocks, the average rejuvenation across four tissues was 54.2%. In other words, the treatment more than halved the epigenetic age.

Their abstract:

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

Evidence that aerobic exercise reverses aging.

Brett et al. show (in mice) that aerobic exercise rejuvenates quiescent skeletal muscle stem cells in old mice and accelerates muscle tissue repair:

Ageing impairs tissue repair. This defect is pronounced in skeletal muscle, whose regeneration by muscle stem cells (MuSCs) is robust in young-adult animals, but inefficient in older organisms. Despite this functional decline, old MuSCs are amenable to rejuvenation through strategies that improve the systemic milieu, such as heterochronic parabiosis [i.e. connecting the circulatory systems of young and old mice). One such strategy, exercise, has long been appreciated for its benefits on healthspan, but its effects on aged stem-cell function in the context of tissue regeneration are incompletely understood. Here, we show that exercise in the form of voluntary wheel running accelerates muscle repair in old mice and improves old MuSC function. Through transcriptional profiling and genetic studies, we discovered that the restoration of old MuSC activation ability hinges on restoration of Cyclin D1, whose expression declines with age in MuSCs. Pharmacologic studies revealed that Cyclin D1 maintains MuSC activation capacity by repressing TGF-β signalling. Taken together, these studies demonstrate that voluntary exercise is a practicable intervention for old MuSC rejuvenation. Furthermore, this work highlights the distinct role of Cyclin D1 in stem-cell quiescence.

Changes in cerebral cortex functional organization in healthy elderly.

Sigh.... Chong et al. offer a picture of how my 78 year old brain is more muddled than that of a ~23 year old male.

SIGNIFICANCE STATEMENT

Cross-sectional studies have demonstrated age-related reductions in the functional segregation and distinctiveness of brain networks. However, longitudinal aging-related changes in brain functional modular architecture and their links to cognitive decline remain relatively understudied. Using graph theoretical and community detection approaches to study task-free functional network changes in a cross-sectional young and longitudinal healthy elderly cohort, we showed that aging was associated with global declines in network segregation, integration, and module distinctiveness, and specific declines in distinctiveness of higher-order cognitive networks. Further, such functional network deterioration was associated with poorer cognitive performance cross-sectionally. Our findings suggest that healthy aging is associated with system-level changes in brain functional modular organization, accompanied by functional segregation loss particularly in higher-order networks specialized for cognition.

Abstract

Healthy aging is accompanied by disruptions in the functional modular organization of the human brain. Cross-sectional studies have shown age-related reductions in the functional segregation and distinctiveness of brain networks. However, less is known about the longitudinal changes in brain functional modular organization and their associations with aging-related cognitive decline. We examined age- and aging-related changes in functional architecture of the cerebral cortex using a dataset comprising a cross-sectional healthy young cohort of 57 individuals (mean ± SD age, 23.71 ± 3.61 years, 22 males) and a longitudinal healthy elderly cohort of 72 individuals (mean ± baseline age, 68.22 ± 5.80 years, 39 males) with 2–3 time points (18–24 months apart) of task-free fMRI data. We found both cross-sectional (elderly vs young) and longitudinal (in elderly) global decreases in network segregation (decreased local efficiency), integration (decreased global efficiency), and module distinctiveness (increased participation coefficient and decreased system segregation). At the modular level, whereas cross-sectional analyses revealed higher participation coefficient across all modules in the elderly compared with young participants, longitudinal analyses revealed focal longitudinal participation coefficient increases in three higher-order cognitive modules: control network, default mode network, and salience/ventral attention network. Cross-sectionally, elderly participants also showed worse attention performance with lower local efficiency and higher mean participation coefficient, and worse global cognitive performance with higher participation coefficient in the dorsal attention/control network. These findings suggest that healthy aging is associated with whole-brain connectome-wide changes in the functional modular organization of the brain, accompanied by loss of functional segregation, particularly in higher-order cognitive networks.

Older adults proactively downregulate anticipated negative affect.

Interesting work from Corbett et al. (open source):

Previous studies have only investigated age-related differences in emotional processing and encoding in response to, not in anticipation of, emotional stimuli. In the current study, we investigated age-related differences in the impact of emotional anticipation on affective responses and episodic memory for emotional images. Young and older adults were scanned while encoding negative and neutral images preceded by cues that were either valid or invalid predictors of image valence. Participants were asked to rate the emotional intensity of the images and to complete a recognition task. Using multivariate behavioral partial least squares (PLS) analysis, we found that greater anticipatory recruitment of the amygdala, ventromedial prefrontal cortex (vmPFC), and hippocampus in older adults predicted reduced memory for negative than neutral images and the opposite for young adults. Seed PLS analysis further showed that following negative cues older adults, but not young adults, exhibited greater activation of vmPFC, reduced activation of amygdala, and worse memory for negative compared with neutral images. To the best of our knowledge, this is the first study to provide evidence that the “positivity effect” seen in older adults’ memory performance may be related to the spontaneous emotional suppression of negative affect in anticipation of, not just in response to, negative stimuli.

Rejuvenating aging human cells.

Nicholas Wade points to important work by Stanford researchers showing they can rejuvenate human cells by reprogramming them back to a youthful state.

A major cause of aging is thought to be the errors that accumulate in the epigenome, the system of proteins that packages the DNA and controls access to its genes.The Stanford team...say their method, designed to reverse these errors and walk back the cells to their youthful state, does indeed restore the cells’ vigor and eliminate signs of aging...The Stanford approach utilizes powerful agents known as Yamanaka factors, which reprogram a cell’s epigenome to its time zero, or embryonic state....In 2006 Dr. Shinya Yamanaka, a stem-cell researcher at Kyoto University, amazed biologists by showing that a cell’s fate could be reversed with a set of four transcription factors — agents that activate genes — that he had identified...the Stanford team described a feasible way to deliver Yamanaka factors to cells taken from patients, by dosing cells kept in cultures with small amounts of the factors.

The Stanford team extracted aged cartilage cells from patients with osteoarthritis and found that after a low dosage of Yamanaka factors the cells no longer secreted the inflammatory factors that provoke the disease. The team also found that human muscle stem cells, which are impaired in a muscle-wasting disease, could be restored to youth. Members of the Stanford team have formed a company, Turn Biotechnologies, to develop therapies for osteoarthritis and other diseases.

Humans were not designed for sitting in chairs.

As I near my 78th birthday I've become increasingly aware of how debilitating activities like sitting and typing this blog post can be. Moving just a bit is a relief (as when I crank my desktop up to standing level or move about just a bit) and exposes how the body's fluxes can become shut down on sitting. This makes me want to pass on the original abstract for work described by Reynolds on how modern hunter-gatherer people deal with periods of being sedentary.  From Raichlen et al.:  

Significance

Inactivity is a growing public health risk in industrialized societies, leading some to suggest that our bodies did not evolve to be sedentary. Here, we show that, in a group of hunter-gatherers, time spent sedentary is similar to that found in industrialized populations. However, sedentary time in hunter-gatherers is often spent in postures like squatting that lead to higher levels of muscle activity than chair sitting. Thus, we suggest human physiology likely evolved in a context that included substantial inactivity, but increased muscle activity during sedentary time, suggesting an inactivity mismatch with the more common chair-sitting postures found in contemporary urban populations.

Abstract

Recent work suggests human physiology is not well adapted to prolonged periods of inactivity, with time spent sitting increasing cardiovascular disease and mortality risk. Health risks from sitting are generally linked with reduced levels of muscle contractions in chair-sitting postures and associated reductions in muscle metabolism. These inactivity-associated health risks are somewhat paradoxical, since evolutionary pressures tend to favor energy-minimizing strategies, including rest. Here, we examined inactivity in a hunter-gatherer population (the Hadza of Tanzania) to understand how sedentary behaviors occur in a nonindustrial economic context more typical of humans’ evolutionary history. We tested the hypothesis that nonambulatory rest in hunter-gatherers involves increased muscle activity that is different from chair-sitting sedentary postures used in industrialized populations. Using a combination of objectively measured inactivity from thigh-worn accelerometers, observational data, and electromygraphic data, we show that hunter-gatherers have high levels of total nonambulatory time (mean ± SD = 9.90 ± 2.36 h/d), similar to those found in industrialized populations. However, nonambulatory time in Hadza adults often occurs in postures like squatting, and we show that these “active rest” postures require higher levels of lower limb muscle activity than chair sitting. Based on our results, we introduce the Inactivity Mismatch Hypothesis and propose that human physiology is likely adapted to more consistently active muscles derived from both physical activity and from nonambulatory postures with higher levels of muscle contraction. Interventions built on this model may help reduce the negative health impacts of inactivity in industrialized populations.