Take β-glucan for new blood vessels

This 2022 cell study investigated yeast cell wall β-glucan’s effects on angiogenesis:

“Angiogenesis, the formation of new blood vessels, is essential for embryonic development and physiological damage repair, such as wound healing and post-ischemic tissue restoration. It is also essential for pathological processes, such as diabetic retinopathy, rheumatoid arthritis, and atherosclerosis.

We evaluated physical and functional interactions of β-glucan with HDAC5, including the scratched wound, tube formation, and rat aortic ring assays. β-glucan-induced HDAC5 pathway mediates cell migration and formation of tubes and microvessels in vitro and ex vivo.

β-glucan angiogenesis

Our findings demonstrate that β-glucan-induced HDAC5 phosphorylation is important in endothelial cell angiogenesis. Further investigations into how β-glucan phosphorylates HDAC5 are required. There is also a need to identify a receptor that specifically binds to β-glucan in vascular endothelial cells.

β-glucan could be useful in developing new strategies in therapeutic angiogenesis for conditions such as cardiovascular disease and diabetes.”

https://www.sciencedirect.com/science/article/abs/pii/S0141813022010273 “Yeast beta-glucan mediates histone deacetylase 5-induced angiogenesis in vascular endothelial cells” (not freely available). Thanks to Dr. Chan-Gi Pack for providing a copy.


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Young gut, young eyes

I’ll highlight this 2022 rodent study findings of effects on eye health:

“We tested the hypothesis that manipulating intestinal microbiota influences development of major comorbidities associated with aging and, in particular, inflammation affecting the brain and retina. Using fecal microbiota transplantation, we exchanged intestinal microbiota of young (3 months), old (18 months), and aged (24 months) mice.

Transfer of aged donor microbiota into young mice accelerates age-associated central nervous system inflammation, retinal inflammation, and cytokine signaling. It promotes loss of key functional protein in the eye, effects which are coincident with increased intestinal barrier permeability.

These detrimental effects can be reversed by transfer of young donor microbiota.

young and aged fmt

We provide the first direct evidence that aged intestinal microbiota drives retinal inflammation, and regulates expression of the functional visual protein RPE65. RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion. Mutations or loss of function are associated with retinitis pigmentosa, and are implicated in age-related macular degeneration.

Our finding that age-associated decline in host retinal RPE65 expression is induced by an aged donor microbiota, and conversely is rescued by young donor microbiota transfer, suggests age-associated gut microbiota functions or products regulate visual function.”

https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-022-01243-w “Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain”


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Unconscious act-outs all the way down

Haven’t curated a study for a while that actually detracted from science. This 2022 human clinical trial that polluted broccoli sprout compounds research provoked me into it:

“Forty-nine participants enrolled, including 26 (53%) females with median use of 20 cigarettes/day. Low and higher-dose broccoli seed and sprout extracts (BSSE) showed a mean bioavailability of 11% and 10%, respectively.

pack years

Participants were treated for 2 weeks with both low and higher-dose BSSE (148 µmol vs. 296 µmol of glucoraphanin daily), separated by a 2-week washout. A multicenter, randomized, placebo-controlled trial evaluating the sustainability of benzene and acrolein detoxification by higher-dose BSSE over 12 weeks is now planned in otherwise healthy, heavy tobacco smokers.”

https://www.mdpi.com/2072-6694/14/9/2129/htm “Randomized Crossover Trial Evaluating Detoxification of Tobacco Carcinogens by Broccoli Seed and Sprout Extract in Current Smokers”


A few unanswered questions:

  • Why would anyone who had a grasp of the reality of their life in this century still smoke? Could their lack of cognition be helped by anyone other than themself?
  • Why would researchers use a suboptimal, ethically compromised product that delivered much less than sulforaphane’s 70-80% bioavailability? Why did they ignore previous research, and neither find nor develop a product that delivered adequate sulforaphane?
  • Why would researchers not consider combined aspects of known insufficient dose / product efficacy / subject sample size / treatment delivery mode and duration? Because sponsors’ money was available, and will continue – regardless of screwups – with another all-expenses-paid, worthless clinical trial?
  • Do “healthy, heavy tobacco smokers” even exist outside of statistical models?
  • Do researchers feel broccoli sprout compounds research is nothing more than a gravy train to keep money flowing to them? If not, why don’t they act differently?
  • Why do I spend even one minute of my one precious life to highlight their and my unconscious act-outs of unsatisfied needs? Maybe if readers understand these misshapenned agendas, they may understand similar circumstances?

Exercise substitutes?

Two papers, starting with a 2022 abstract of an ongoing in vitro study with rodent cells:

“Exercise mimetics may target and activate the same mechanisms that are upregulated with exercise administration alone. This is particularly useful under conditions where contractile activity is compromised due to muscle disuse, disease, or aging.

Sulforaphane and Urolithin A represent our preliminary candidates for antioxidation and mitophagy, respectively, for maintaining mitochondrial turnover and homeostasis. Preliminary results suggest that these agents may be suitable candidates as exercise mimetics, and set the stage for an examination of synergistic effects.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R3745 “Exercise mimicry: Characterization of nutraceutical agents that may contribute to mitochondrial homeostasis in skeletal muscle” (study not available)


A second 2022 paper reviewed what’s known todate regarding urolithins:

“Urolithins (Uros) are metabolites produced by gut microbiota from the polyphenols ellagitannins (ETs) and ellagic acid (EA). ETs are one of the main groups of hydrolyzable tannins. They can occur in different plant foods, including pomegranates, berries (strawberries, raspberries, blackberries, etc.), walnuts, many tropical fruits, medicinal plants, and herbal teas, including green and black teas.

Bioavailability of ETs and EA is very low. Absorption of these metabolites could be increased by co-ingestion with dietary fructooligosaccharides (FOS).

Effects of other experimental factors: post-intake time, duration of administration, diet type (standard and high-fat), and ET dosage (without, low, and high ET intake) in ETs metabolism were evaluated in blood serum and urine of rats consuming strawberry phenolics. Highest concentrations were obtained after 2–4 days of administration.

Various crucial issues need further research despite significant evolution of urolithin research. Overall, whether in vivo biological activity endorsed to Uros is due to each specific metabolite and(or) physiological circulating mixture of metabolites and(or) gut microbial ecology associated with their production is still poorly understood.

  • Ability of Uros to cross the blood-brain barrier and the nature of metabolites and concentrations reached in brain tissues need to be clarified.
  • Specific in vivo activity for each free and conjugated Uro metabolite is unknown. Studies on different Uro metabolites and their phase-II conjugates are needed to understand their role in human health.
  • Evidence on safety and impact of Uros on human health is still scarce and only partially available for Uro-A.
  • It is unknown whether there are potential common links between gut microbial ecologies of the two unambiguously described metabotypes so far, i.e., equol (isoflavones) and Uros (ellagitannins).
  • Gut microbes responsible for producing different Uros still need to be better identified and characterized, and biochemical pathways and enzymes involved.”

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202101019 “Urolithins: a Comprehensive Update on their Metabolism, Bioactivity, and Associated Gut Microbiota”


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Blood pressure and brain age

This 2021 human study investigated associations between blood pressure and MRI measurements:

“We estimated how a validated measure of brain health related to changes in BP over a period of 12 years. The main findings of this study were:

  • All BP measures were associated with older BrainAGE;
  • Associations were stronger in men than women;
  • Associations were not only detected in hypertensive individuals but across the whole BP range; and
  • Individuals with optimal blood pressure (110/70) presented with the lowest BrainAGE.

These findings support the view that maintaining blood pressure in an optimal range (SBP < 115, DBP < 75) across the lifespan starting before mid-life (i.e., in early adulthood and before) is essential to maintain good cerebral health.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523821/ “Optimal Blood Pressure Keeps Our Brains Younger”


I’m making progress on a New Year’s resolution. Here’s how I started 2022:

bp 2021

Current readings show both lower averages and variability:

bp 2022

~12% decreases in average systolic (111 – 126)/126 and diastolic (69 – 78)/78 pressures over 135 days. 🙂 I measure blood pressure every day right after I wake up.

What caused these decreases? Continuing what I was already doing. The top factor is probably that at lunch every day I take 600 mcg of Vitamin K2 MK-7 along with a gram of flax oil.

I started taking K2 this time last year per Vitamin K2 – What can it do? Apparently its effects are gradual and develop slowly. Vitamin K2 and hypertension may also be relevant.

I came across this study from its mention in today’s video:

Coffee improves information’s signal-to-noise ratio

This 2022 rodent study investigated caffeine’s effects:

“A majority of molecular and neurophysiological studies explored the impact of acute rather than repeated exposure to caffeine. We show that, in bulk tissue analysis, chronic caffeine treatment reduced metabolic processes related to lipids, mitochondria, and translation in mouse hippocampus. In sharp contrast to what was observed in bulk tissue, we found that caffeine induced a neuronal autonomous epigenomic response related to synaptic plasticity activation.

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Regular caffeine intake exerts a long-term effect on neuronal activity/plasticity in the adult brain, lowering metabolic-related processes, and simultaneously finely tuning activity-dependent regulations. In non-neuronal cells, caffeine decreases activities under basal conditions, and improves signal-to-noise ratio during information encoding in brain circuits, contributing to bolster salience of information.

Overall, our data prompt the novel concept that regular caffeine intake promotes a more efficient ability of the brain to encode experience-related events. By coordinating epigenomic changes in neuronal and non-neuronal cells, regular caffeine intake promotes a fine-tuning of metabolism in resting conditions.”

https://www.jci.org/articles/view/149371 “Caffeine intake exerts dual genome-wide effects on hippocampal metabolism and learning-dependent transcription”


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Eat broccoli sprouts for stress

This 2022 review subject was aspects of sulforaphane regulating stress:

“Sulforaphane (SFN) shows great versatility in turning on different cellular responses. This isothiocyanate acts as a master regulator of cellular homeostasis due to its antioxidant response and cytoplasmic, mitochondrial, and endoplasmic reticulum (ER) protein modulation. SFN acts as an effective strategy to counteract oxidative stress, apoptosis, and ER stress, among others as seen in different injury models.

The ER is a complex membrane system, involved in several cellular processes including lipid synthesis and distribution, and Ca2+ storage and signaling. The ER is highly dynamic and changes according to cellular demand (e.g., hypoxia, mitochondrial dysfunction, or oxidative stress), leading to accumulation of unfolded or misfolded proteins in ER lumen, known as ER stress.

ER stress is buffered by unfolded protein response (UPR) activation, a homeostatic signaling network that orchestrates recovery of ER function by decreasing the burden of misfolded proteins. If stress signals continue it could lead to apoptosis activation.

Studies highlight a close interrelationship between ER stress and oxidative stress, two events driven by the accumulation of reactive oxygen species. Responses to stress inevitably perpetuate, and act as a vicious cycle that triggers development of different pathologies, such as cardiovascular diseases, neurodegenerative diseases, and others.

The PERK/Nrf2 pathway communicates oxidative stress and ER stress:

1-s2.0-S0024320522002545-ga1_lrg

SFN couples oxidative and ER stress to promote cellular redox homeostasis. Further studies in animal and human models are required to elucidate pathways and proteins involved in differential responses orchestrated by SFN, emphasizing that responses will depend on cell type and kind of pathology, as well as SFN concentration.”

https://www.sciencedirect.com/science/article/abs/pii/S0024320522002545 “Role of sulforaphane in endoplasmic reticulum homeostasis through regulation of the antioxidant response” (not freely available) Thanks to Dr. Alejandro Silva for providing a copy.


Every hand’s a winner, and every hand’s a loser has more on UPR.

Brain changes

This 2022 human study investigated healthy young adult brain changes using MRI and epigenetic clock technologies:

“We aimed to characterize the association of epigenetic age (i.e. estimated DNA methylation age) and its acceleration with surface area, cortical thickness, and volume in healthy young adults. It is largely unknown how accelerated epigenetic age affects multiple cortical features among young adults from 19 to 49 years. Prior findings imply not only that these dynamic changes reveal different aspects of cortical aging, but also that chronological age itself is not a reliable factor to understand the process of cortical aging.

accelerated epigenetic age vs brain features

Seventy-nine young healthy individuals participated in this study. Findings of our study should be interpreted within the context of relatively small sample size, without older adults, and with epigenetic age assessed from saliva.

Additional and unique regional changes due to advanced and accelerated epigenetic age, compared to chronological age-related changes, suggest that epigenetic age could be a viable biomarker of cortical aging. Longitudinal and cross-sectional studies with a larger sample and wider age range are necessary to characterize ongoing effects of epigenetic cortical aging, not only for healthy but also for pathological aging.”

https://doi.org/10.1093/cercor/bhac043 “The effects of epigenetic age and its acceleration on surface area, cortical thickness, and volume in young adults” (not freely available) Thanks to Dr. Yong Jeon Cheong for providing a copy.

Who Americans are

A 2022 review of an Admiral Hyman Rickover biography:

“Why is the US populated by so many unreasonable, opposite, entrepreneurial thinkers? We’re not a race as much as we are or we’re descended from a collection of people from around the world who somewhat uniquely decided to risk everything (including their lives) to cross oceans and borders in pursuit not of security, but freedom.

Americans aren’t (name your country) as much as they’re outliers from those countries who had the drive and courage to make the ultimate entrepreneurial leap: starting over in an all-new place. Rickover was one of them.

He made sure that seagoing accommodations were far better for submariners who operated his nuclear subs relative to the horrendous conditions that prevailed in the diesel submarines of the past. He said ‘Don’t tell me what’s going great. I only want to know what’s going wrong.’

His family escaping horrid poverty didn’t look too appealing upon arrival at Ellis Island, but that’s the point. The U.S. won the so-called War on Poverty in the late 18th century by virtue of principles of freedom that it was founded upon. Poverty isn’t cured by handouts as much as freedom is always the answer.”

https://www.realclearmarkets.com/articles/2022/02/24/book_review_marc_wortmans_excellent_admiral_hyman_rickover_818373.html


I didn’t have positive expectations of an interview forty years ago with Admiral Rickover for a position on his staff. I was selected for being top of my Supply Corps class, but wasn’t the Type A personality he wanted for his purposes.

It was still instructive to talk with a person who thoroughly understood what he wanted and how to get there.

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A healthspan improvement

Two 2022 publishments, starting with an excerpt from an informative interview with the Director of one of the three Interventions Testing Program centers:

“A paper submitted this week is one in which we tried a combination of rapamycin plus acarbose. Rapamycin works very well in male and female mice, while acarbose works significantly in both sexes but has a much stronger effect in males.

What we found in males is that when you give rapamycin and acarbose together, you do better than either rapamycin by itself or acarbose by itself. That combination of drugs together gives male survival a 29% boost.

That’s the largest percentage increase we’ve seen in males or females. This combination is the best thing we’ve ever had for either sex.

When you give acarbose and rapamycin together to females, they don’t do any better or any worse than on rapamycin alone. This is not too surprising because acarbose gives only a small effect in females. We expected it wouldn’t have a big boost over rapamycin alone in female animals, and that’s what we found.”

https://www.lifespan.io/news/prof-richard-miller-on-the-intervention-testing-program/


The study mentioned above:

“C57BL/6 mice were fed a cocktail diet containing one-half the dose of each drug compared to full dose cocktail diet and control diet. Half-dose drug cocktail was just as effective as full dose in preventing age-related cognitive impairment, but was less effective in other physical performance tests. Half-dose cocktail also had no effect on reducing pathological lesions.

Rapamycin was the major contributor for the cocktail’s effect on suppressing cognitive impairment. Decreased neuronal activation and impaired cognitive performance during aging occurs in both humans and rodents. Chronic mTOR attenuation by rapamycin has shown benefits of restoring deficits in neurovascular coupling response and cerebrovascular dysfunction in aging rodent models.

C57BL/6 female mice fed chow with acarbose performed equally well in grip strength as females fed chow with cocktail. That this sex-dependent result in strength performance was not seen in cocktail treated mice suggests that rapamycin and phenylbutyrate contributed in some way.

grip strength

HET3 4-way cross is a useful strain to help validate effects of the cocktail on aging parameters in C57BL/6 mice. HET3 mice were tested in the same manner, age, and timing as C57BL/6 mice, but only with the drug cocktail compared to control chow.

grip strength het3 mice

Grip strength force was normalized by body weight measured on the testing date so that peak force was expressed relative to body weight.

The drug cocktail was very effective in delaying progression of age-related pathology in all organs examined. We view this as a vital component of the study since mice were treated for only three months.

Administration of a cocktail has a major advantage over any individual drug tested in this study. A combination of three drugs previously shown to enhance lifespan and health span in mice is able to delay aging phenotypes more effectively and more robustly than any individual drug in the cocktail when started at middle age and given for a short period of time.”

https://www.nature.com/articles/s41598-022-11229-1 “Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice”


It makes evolutionary sense for male mice to benefit more from anti-aging treatments than females.  Per How well do single-mother rodent studies inform us about human fathers?

“The Rattus and Mus genera used in almost all rodent research aren’t part of the 6% in which fathers also provide offspring care.”

There probably isn’t an evolutionary advantage for male mice to live much longer after sperm donation. Female mice don’t cache sperm.

It’s similar to studies in which treatments only benefited subjects who started out deficient. This interview hinted at how females’ healthspans and lifespans were already evolutionarily protected, with only male mice benefiting from 17α-estradiol treatment.

Female protection may have limits in humans. For example, most whale species don’t experience menopause. In those that do, like Orca, menopause is thought to be evolutionarily determined in order to keep females’ children from competing for resources with females’ grandchildren and great-grandchildren. That’s a hypothesis, though, as those species’ male lifespans aren’t adequately measured.

Rodent research and development on interventions and doses continues. 37 months is a human equivalent to this study’s 3-month treatment. What will effective anti-aging treatments be for humans?


More strange birds

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Young immune system, young brain

This 2022 study investigated brain aging:

“We aimed to explore key genes underlying cognitively normal brain aging and its potential molecular mechanisms. Cellular and molecular mechanisms of brain aging are complex and mainly include:

  1. Dysfunction of mitochondria;
  2. Accumulation of oxidatively damaged proteins, nucleic acids, and lipids in brain cells;
  3. Disorders of energy metabolism;
  4. Impaired ‘waste disposal’ mechanism (autophagosome and proteasome functionality);
  5. Impaired signal transduction of adaptive stress response;
  6. Impaired DNA repair;
  7. Abnormal neural network activity;
  8. Imbalance of neuronal Ca2+ processing;
  9. Stem cell exhaustion; and
  10. Increased inflammation.

mrna brain expression

Expression of CD44, CD93, and CD163 mRNA detected by qPCR in hippocampal tissue of cognitively normal aged and young mice.

Underlying molecular mechanisms for maintaining healthy brain aging are related to decline of immune-inflammatory responses. CD44, CD93, and CD 163 are potential biomarkers.”

https://www.frontiersin.org/articles/10.3389/fnagi.2022.833402/full “Identification of Key Biomarkers and Pathways for Maintaining Cognitively Normal Brain Aging Based on Integrated Bioinformatics Analysis”


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Thyroid function

This 2022 review subject was thyroid function changes:

“Circulating concentrations of thyrotropin (TSH) and thyroxine (T4) are tightly regulated. Each individual has setpoints for TSH and free T4 which are genetically determined, and subject to environmental and epigenetic influence.

What is normal for one individual may not be normal for another, even within conventional definitions of euthyroidism. Notably, circulating TSH exists in several different isoforms with varying degrees of glycosylation, sialylation, and sulfonation which affect tissue availability and bioactivity. This is not reflected in immunoreactive TSH concentrations determined by routine laboratory assays.

enm-2022-1463f2

TSH and free T4 relationship analyzed by age in 120,403 patients who were not taking thyroxine treatment. Median TSH for each free T4 integer value (in pmol/ L) was calculated, then plotted as 20-year age bands in adults. Dotted horizontal and vertical lines mark the TSH reference range (0.4 to 4.0 mU/L) and free T4 reference range (10 to 20 pmol/L), respectively.

Mild TSH elevation in older people does not predict adverse health outcomes. In fact, higher TSH is associated with greater life expectancy, including extreme longevity.

In older people, TSH increases with aging without an accompanying fall in free T4. Clinical guidelines now recommend against routine levothyroxine treatment in older people with mild subclinical hypothyroidism.”

https://e-enm.org/journal/view.php?doi=10.3803/EnM.2022.1463 “Thyroid Function across the Lifespan: Do Age-Related Changes Matter?”


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Reinvigorated

A follow-on to Beginning of the cure for aging:

“So, I rubbed a small sample of E5 on my right hand and after three days the results were visible. The skin on the treated hand is visibly thicker and lighter. Certainly not a definitive test, but wow, my hand looks decades younger. Dr. Harold Katcher

maos

Hi all,

I applied a little bit of an old freeze-dried prep – there’s no trick here Jay (how could there be), my right-hand looks 30 years younger, even my veins are narrower and less prominent, (I wonder if they’ve let go of their calcification) they also seem less visible because the skin appears thicker

Obviously, the experiment needs to be tried on many people, but I’m certain their reaction will be the same as mine. The interesting thing is, as you noted Jay that the E5 used was essentially just the precipitate, (so therefore crude), but if only for external use, it would not have to meet the same criteria for use as something used internally.

I’m looking at my hands right now and am amazed, a real miracle. I suppose it will fade (as my blood contains pro-aging factors) – but surprisingly, we now have real evidence that E5 works on people. Yesterday Kavita said it doesn’t look like both hands could belong to the same person).

I only applied a small bit to the upper surface of my right hand, nothing more. It was actually historic.

Best to all, Harold


One thing I remember about my father’s parents was spots on their hands and forearms. As a child, I didn’t understand how that happened. After growing up in Miami, and visiting dermatologists 2-3 times a year decades later, it’s apparent.

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Vitamin D and pain

This 2022 human study investigated epigenetic clock associations:

“We assessed the potential relationship of Vitamin D’s effects on pain intensity and disability through associations in epigenetic aging in individuals with and without knee osteoarthritis (KOA). We hypothesized that associations between Vitamin D levels with pain intensity and interference in persons with KOA would be significantly mediated by epigenetic aging.

As a whole, the sample had a mean Vitamin D serum level of 26.7 ng/mL (± 12.8 ng/mL). The mean AgeAccelGrim was 2.4 years (± 5.6 years). There were no significant differences in Vitamin D levels between sex, race, and study site categories.

There was a significant difference in Vitamin D levels between the pain groups, with individuals in the High Impact Pain group showing significantly lower mean levels of Vitamin D (24.01 ng/mL) compared to the Low Impact Pain (28.30 ng/mL) and No Pain (27.30 ng/mL) groups.

vitamin d and pain

Data from this study highlight the important role that Vitamin D plays within the genomic environment, as well as in relation to health outcomes including pain intensity and disability.”

https://link.springer.com/article/10.1007/s12603-022-1758-z “Accelerated Epigenetic Aging Mediates the Association between Vitamin D Levels and Knee Pain in Community-Dwelling Individuals” (not freely available)


It’s good to see a study relating biological age to nutrition status. I didn’t see much discussion of other obvious factors involved in either pain or biological age in their limitations paragraph.

Subjects’ Vitamin D 26.7 ng/mL ± 12.8 ng/mL status indicated that most didn’t spend a few cents every day for their own one precious life. And Vitamin D supplementation wasn’t an exclusion criterion.

The local fire and rescue squad came last Friday to take away a younger neighbor’s body who died overnight. Last I talked with them, they were at least 50 pounds overweight and never exercised. Expressed condolences to their spouse, but wasn’t shocked.

I don’t live in a community-dwelling situation (old people who live on their own as opposed to those taken care of in nursing homes) like this study’s subjects. My youngest neighbors are in their twenties.

Nature hasn’t cared about our lives after our early teens, because we survived long enough to reproduce. What happens in our lives after puberty is largely up to each individual.

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