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Dean Pomerleau

Cold Exposure & Other Mild Stressors for Increased Health & Longevity

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On 6/9/2021 at 4:00 PM, Saul said:

The takeaway:  Life expectancy is longer in States with Higher Income.

True. Medical care has advanced considerably, at a price.

Yet the Blue Zones are all in temperate to warm climates, often dirt poor, like Sardinia and Okinawa.

The oldest person born in the North I could find was Christian Mortensen, but he actually spent most of his life in balmy California....

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BAT Hypertrophy after CR Correlates with Lifespan Benefits

I've suggested repeatedly on this thread (e.g. here, herehere and here) that there may be a synergy between CR and cold exposure (CE) when it comes to lifespan and healthspan. In fact, I've said that the benefits of CR may require the simultaneous exposure to cold environmental conditions.

This new study [1] posted by Al (thanks Al!) seems like pretty good evidence to support this hypothesis, and that the effect is mediated by thermogenic Brown Adipose Tissue (BAT).

First a little background. We've discussed several times in this thread and elsewhere (e.g. here) the evidence that CR works to extend lifespan in some strains of mice, while shortening lifespan in others. Here is the graph from [2] of the impact of CR on lifespan of various strains of female mice:

20210716_135142.jpg

Some strains, like 89 (green highlight above) have their lifespan dramatically extended by 40% CR. Some, like strain 114 (red highlight) live shorter lives when subjected to 40% CR. And some, like strain 48 (yellow), don't show much difference in lifespan on 40% CR.

It was subsequently shown in [3] (by the same authors as [2]) that in these same strains of mice, those strains that maintain their body temperature better when exposed to "normal" (i.e. chilly for mice, ~72degF) housing conditions were the ones that benefited from CR. Obviously that is a tantalizing hint that the ability to boost thermogenic BAT when subjected to CR + CE may be key for extending lifespan at least in these strains, as I discussed here.

Further evidence for the importance of BAT when it comes to longevity in the face of CR + CE was demostrated in [4] (discussed here), which showed that BAT was the only tissue whose mass was increased when subjected to CR. As you can see from this table from [4], every other tissue except the brain and a few muscles (which stayed the same) shrunk in 40% CR mice relative to its size under ad lib feeding at both 6 months and 26 months of age, while BAT mass more than doubled:

Screenshot_20210716-143606_Chrome.jpg

 

Now we come to this new study [1], which looked at three of the strains of mice from the original study [2] whose response to CR differed - specifically the strains of mice I highlighted above with green (longevity benefitted from CR), yellow (no change in longevity from CR) and red (shortened longevity from CR). Note the three strains had similar lifespans when fed AL; it was only when subjected to CR that their lifespans diverged.

So what did they find differed between these strains besides longevity? Most relevant for this thread and my hypothesis, they found that in the green, long-lived strain and to a lesser extent the yellow strain, BAT mass was increased when the mice were subjected to CR + CE, while in the red strain whose lifespan was shortened by CR, their BAT mass was unchanged relative to AL. Below is the (color coded) set of graphs from [1]. All three strains lost weight on CR (graph A), but only the green strain dramatically boosted BAT mass as a percent of body mass (gragh D) as a result of CR:

20210716_145722.jpg 

So once again we see the importance for longevity of preserving or even increasing BAT when subjected to CR + CE.

In this rather geeky and speculative post, I hypothesized that in order to stay warm, strains of mice that don't increase BAT when subjected to CR + CE have to maintain lots of highly unsaturated long-chain fatty acids in their cell and especially mitochondrial membranes (contra the usual effect of CR which is to increase membrane saturation), thereby making their membranes "leakier" to protons (which generates heat) but also making said membranes more susceptible to peroxidation, thereby harming their longevity. In contrast, strains which boost BAT when subjected to CR + CE can keep warm via BAT-thermogenesis and so can keep their membranes "tight" (i.e. saturated) and therefore less susceptible to peroxidation, increasing lifespan.

In (qualified) support of this hypothesized mechanism, the authors of [1] found that only green strain (but not the red strain) showed the usual CR-induced increase in membrane saturation at least in the tissue they measured (white adipose tissue).

One surprise in [1] was that only the red strain showed improved glucose tolerance when subjected to CR, which seems to contradict lots of evidence from elsewhere (and personal experience) that cold exposure and extra BAT improves glucose metabolism.

But whatever the mechanism, [1] provides further evidence that the ability to boost BAT when subjected to CR + CE is integral to the life-extending effect of the combination, and it goes without saying (since I've said it so many times before :-)), that CR in rodents only appears to extend longevity when combined with CE.

--Dean

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[1] Strain-specific metabolic responses to long-term caloric restriction in female ILSXISS recombinant inbred mice.
Mulvey L, Wilkie SE, Griffiths K, Sinclair A, McGuinness D, Watson DG, Selman C.
Mol Cell Endocrinol. 2021 Jul 8:111376. doi: 10.1016/j.mce.2021.111376. Online ahead of print.
PMID: 34246728 Review.
Abstract
The role that genetic background may play in the responsiveness of organisms to interventions such as caloric restriction (CR) is underappreciated but potentially important. We investigated genetic background on a suite of metabolic parameters in female recombinant inbred ILSXISS mouse strains previously reported to show divergent lifespan responses to 40% CR (TejJ89-lifespan extension; TejJ48-lifespan unaffected; TejJ114-lifespan shortening). Body mass was reduced across all strains following 10 months of 40% CR, although this loss (relative to ad libitum controls) was greater in TejJ114 relative to the other strains. Gonadal white adipose tissue (gWAT) mass was similarly reduced across all strains following 40% CR, but brown adipose tissue (BAT) mass increased only in strains TejJ89 and TejJ48. Surprisingly, glucose tolerance was improved by CR only in TejJ114, while strains TejJ89 and TejJ114 were relatively hyperinsulinemic following CR relative to their AL controls. We subsequently undertook an unbiased metabolomic approach in gWAT and BAT tissue from strains TejJ89 and TejJ114 mice under AL and 40% CR. gWAT from TejJ89 showed a significant reduction in several long chain unsaturated fatty acids following 40% CR, but gWAT from TejJ114 appeared relatively unresponsive to CR, with far fewer metabolites changing. Phosphatidylethanoloamine lipids within the BAT were typically elevated in TejJ89 following CR, while some phosphatidylglycerol lipids were decreased. However, BAT from strain TejJ114 again appeared unresponsive to CR. These data highlight strain-specific metabolic differences exist in ILSXISS mice following CR. We suggest that precisely how different fat depots respond dynamically to CR may be an important factor in the variable longevity under CR observed in these mice.
Keywords: Dietary restriction; Genetic heterogeneity; Metabolomics; White adipose tissue; brown adipose tissue.

 

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[2] Exp Gerontol. 2010 Sep;45(9):691-701. doi: 10.1016/j.exger.2010.04.008. Epub 

2010 May 7.

Genetic dissection of dietary restriction in mice supports the metabolic 
efficiency model of life extension.

Rikke BA(1), Liao CY, McQueen MB, Nelson JF, Johnson TE.

Author information:
(1)Institute for Behavioral Genetics, University of Colorado at Boulder, 
Boulder, CO 80309, USA. rikke@colorado.edu

Dietary restriction (DR) has been used for decades to retard aging in rodents, 
but its mechanism of action remains an enigma. A principal roadblock has been 
that DR affects many different processes, making it difficult to distinguish 
cause and effect. To address this problem, we applied a quantitative genetics 
approach utilizing the ILSXISS series of mouse recombinant inbred strains. 
Across 42 strains, mean female lifespan ranged from 380 to 1070days on DR (fed 
60% of ad libitum [AL]) and from 490 to 1020days on an AL diet. Longevity under 
DR and AL is under genetic control, showing 34% and 36% heritability, 
respectively. There was no correlation between lifespans on DR and AL; thus 
different genes modulate longevity under the two regimens. DR lifespans are 
significantly correlated with female fertility after return to an AL diet after 
various periods of DR (R=0.44, P=0.006). We assessed fuel efficiency (FE, 
ability to maintain growth and body weight independent of absolute food intake) 
using a multivariate approach and found it to be correlated with longevity and 
female fertility, suggesting possible causality. We found several quantitative 
trait loci responsible for these traits, mapping to chromosomes 7, 9, and 15. We 
present a metabolic model in which the anti-aging effects of DR are consistent 
with the ability to efficiently utilize dietary resources.

Copyright 2010 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.exger.2010.04.008
PMCID: PMC2926251
PMID: 20452416 [Indexed for MEDLINE]

-----------------

[3] Aging Cell. 2011 Aug;10(4):629-39. doi: 10.1111/j.1474-9726.2011.00702.x. Epub

2011 Apr 25.

Fat maintenance is a predictor of the murine lifespan response to dietary
restriction.

Liao CY(1), Rikke BA, Johnson TE, Gelfond JA, Diaz V, Nelson JF.

Author information: 
(1)Department of Physiology, University of Texas Health Science Center, San
Antonio, TX 78229, USA.

Dietary restriction (DR), one of the most robust life-extending manipulations, is
usually associated with reduced adiposity. This reduction is hypothesized to be
important in the life-extending effect of DR, because excess adiposity is
associated with metabolic and age-related disease. Previously, we described
remarkable variation in the lifespan response of 41 recombinant inbred strains of
mice to DR, ranging from life extension to life shortening. Here, we used this
variation to determine the relationship of lifespan modulation under DR to fat
loss. Across strains, DR life extension correlated inversely with fat reduction, 
measured at midlife (males, r= -0.41, P<0.05, n=38 strains; females, r= -0.63,
P<0.001, n=33 strains) and later ages. Thus, strains with the least reduction in 
fat were more likely to show life extension, and those with the greatest
reduction were more likely to have shortened lifespan. We identified two
significant quantitative trait loci (QTLs) affecting fat mass under DR in males
but none for lifespan, precluding the confirmation of these loci as coordinate
modulators of adiposity and longevity. Our data also provide evidence for a QTL
previously shown to affect fuel efficiency under DR. In summary, the data do not 
support an important role for fat reduction in life extension by DR. They suggest
instead that factors associated with maintaining adiposity are important for
survival and life extension under DR.

© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society
of Great Britain and Ireland.

DOI: 10.1111/j.1474-9726.2011.00702.x 
PMCID: PMC3685291
PMID: 21388497  [Indexed for MEDLINE]

-------------

[4] 

Mech Ageing Dev. 2005 Jun-Jul;126(6-7):783-93. Epub 2005 Mar 16.
 
Energy expenditure of calorically restricted rats is higher than predicted from
their altered body composition.
 
Selman C(1), Phillips T, Staib JL, Duncan JS, Leeuwenburgh C, Speakman JR.
 
Author information: 
(1)University of Florida, Department of Aging and Geriatric Research, College of 
Medicine, Gainesville, 32608, USA. c.selman@ucl.ac.uk
 
Debate exists over the impact of caloric restriction (CR) on the level of energy 
expenditure. At the whole animal level, CR decreases metabolic rates but in
parallel body mass also declines. The question arises whether the reduction in
metabolism is greater, smaller or not different from the expectation based on
body mass change alone. Answers to this question depend on how metabolic rate is 
normalized and it has recently been suggested that this issue can only be
resolved through detailed morphological investigation. Added to this issue is the
problem of how appropriate the resting energy expenditure is to characterize
metabolic events relating to aging phenomena. We measured the daily energy
demands of young and old rats under ad libitum (AD) food intake or 40% CR, using 
the doubly labeled water (DLW) method and made detailed morphological examination
of individuals, including 21 different body components. Whole body energy demands
of CR rats were lower than AD rats, but the extent of this difference was much
less than expected from the degree of caloric restriction, consistent with other 
studies using the DLW method on CR animals. Using multiple regression and
multivariate data reduction methods we built two empirical predictive models of
the association between daily energy demands and body composition using the ad
lib animals. We then predicted the expected energy expenditures of the CR animals
based on their altered morphology and compared these predictions to the observed 
daily energy demands. Independent of how we constructed the prediction, young and
old rats under CR expended 30 and 50% more energy, respectively, than the
prediction from their altered body composition. This effect is consistent with
recent intra-specific observations of positive associations between energy
metabolism and lifespan and theoretical ideas about mechanisms underpinning the
relationship between oxygen consumption and reactive oxygen species production in
mitochondria.
 
PMID: 15888333
 

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Excess dietary carbohydrate affects mitochondrial integrity as observed in brown adipose tissue.
Waldhart AN, Muhire B, Johnson B, Pettinga D, Madaj ZB, Wolfrum E, Dykstra H, Wegert V, Pospisilik JA, Han X, Wu N.
Cell Rep. 2021 Aug 3;36(5):109488. doi: 10.1016/j.celrep.2021.109488.
PMID: 34348139
https://www.cell.com/cell-reports/pdf/S2211-1247(21)00915-3.pdf
Abstract
Hyperglycemia affects over 400 million individuals worldwide. The detrimental health effects are well studied at the tissue level, but the in vivo effects at the organelle level are poorly understood. To establish such an in vivo model, we used mice lacking TXNIP, a negative regulator of glucose uptake. Examining mitochondrial function in brown adipose tissue, we find that TXNIP KO mice have a lower content of polyunsaturated fatty acids (PUFAs) in their membrane lipids, which affects mitochondrial integrity and electron transport chain efficiency and ultimately results in lower mitochondrial heat output. This phenotype can be rescued by a ketogenic diet, confirming the usefulness of this model and highlighting one facet of early cellular damage caused by excess glucose influx.
Keywords: BAT; PUFA; TXNIP; cold stress; glucose; ketogenic diet; lipid; mitochondria.

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This paper shows brown fat activity is higher in the morning. Taking a cold shower or eating breakfast earlier in the day can trigger brown fat function much more than in the evening.

https://www.nature.com/articles/s41366-021-00927-x

Abstract

Background/objectives

Disturbed circadian rhythm is associated with an increased risk of obesity and metabolic disorders. Brown adipose tissue (BAT) is a site of nonshivering thermogenesis (NST) and plays a role in regulating whole-body energy expenditure (EE), substrate metabolism, and body fatness. In this study, we examined diurnal variations of NST in healthy humans by focusing on their relation to BAT activity.

Methods

Forty-four healthy men underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography and were divided into Low-BAT and High-BAT groups. In STUDY 1, EE, diet-induced thermogenesis (DIT), and fat oxidation (FO) were measured using a whole-room indirect calorimeter at 27 °C. In STUDY 2, EE, FO, and skin temperature in the region close to BAT depots (Tscv) and in the control region (Tc) were measured at 27 °C and after 90 min cold exposure at 19 °C in the morning and in the evening.

Results

In STUDY 1, DIT and FO after breakfast was higher in the High-BAT group than in the Low-BAT group (P < 0.05), whereas those after dinner were comparable in the two groups. FO in the High-BAT group was higher after breakfast than after dinner (P < 0.01). In STUDY 2, cold-induced increases in EE (CIT), FO, and Tscv relative to Tc in the morning were higher in the High-BAT group than in the Low-BAT group (P < 0.05), whereas those after dinner were comparable in the two groups. CIT in the High-BAT group tended to be higher in the morning than in the evening (P = 0.056).

Conclusion

BAT-associated NST and FO were evident in the morning, but not in the evening, suggesting that the activity of human BAT is higher in the morning than in the evening, and thus may be involved in the association of an eating habit of breakfast skipping with obesity and related metabolic disorders.

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