1 reply to this topic

[ta5]

I thought this was a nice review. The full text is available. 

 

Nucleus. 2014 Jan-Feb;5(1):56-65.

The fine line between lifespan extension and shortening in response to caloric restriction.

Szafranski K1, Mekhail K2.

Caloric restriction (CR) is generally linked to lifespan extension in various organisms and may limit age-associated diseases. Processes through which caloric restriction promotes lifespan include obesity-countering weight loss, increased DNA repair, control of ribosomal and telomeric DNA repeats, mitochondrial regulation, activation of antioxidants, and protective autophagy. Several of these protective cellular processes are linked to the suppression of TOR (target of rapamycin) or the activation of sirtuins. In stark contrast, CR fails to extend or even shortens lifespan in certain settings. CR-dependent lifespan shortening is linked to weight loss in the non-obese, mitochondrial hyperactivity, genomic inflexibility, and several other processes. Deciphering the balance between positive and negative effects of CR is critical to understanding its ultimate impact on aging. This knowledge is especially needed in order to fulfil the promise of using CR or its mimetic drugs to counteract age-associated diseases and unhealthy aging.

PMID: 24637399

 

Here are a few paragraphs...

Introduction

 

[...] However, contrary to the well-documented positive effects of caloric restriction, several studies reported caloric restriction to be neutral or even detrimental to lifespan. For example, studies have found that caloric restriction regimens fail to impact lifespan in rhesus monkeys,7 wild mice,8 medflies,9 an isolate of the nematode C. Remanai,10 the spider L. Hasselti,11 and some yeast strains.12,13 Even more striking, CR actually shortened lifespan in several models including houseflies,14 male butterflies,15 the rotifer Cephalodella sp.,16 ILSXISS mice strains,17,18 and some yeast strains (Table 1).13 The work done with ILSXISS mice is particularly poignant. A meta-analysis of all mice studies excluding the ILSXISS strains reveals an average CR-dependent increase in lifespan of 15%.19 When the ILSXISS strains are included in the meta-analysis the average increase in lifespan drops to 2.9%.19 The ILSXISS studies set CR at 60% of AL intake in agreement with common standards in the field but it remains possible that more or less substantial restrictions may promote the lifespan of both ILSXISS and other mice strains. Taken together, these studies indicate that standard caloric restriction regimens do not universally promote longevity in various organisms. In other words, several more variables may exist within the equation determining the impact of CR on lifespan than originally anticipated. [...]

 

Reduction of Body Weight under CR Can Positively or Negatively Affect Lifespan

 

[...] As they start following CR regimens, obese individuals typically increase their lifespan as they lose fat mass. Simply put, this is because obesity is correlated with a number of age-associated pathologies such as cardiovascular disease and diabetes.29,30 Consistent with this rationale, in obese human males, CR reduces body fat while also significantly decreasing obesity-related pathologies such as high blood pressure and chronic inflammation.31 In addition, in obese mice, the combination of CR and omega-3-polyunsaturated fatty acid intake simultaneously counteracts adiposity and chronic inflammation.32 Thus, within obesity settings, CR-mediated weight loss is generally beneficial.

 

In contrast, fat loss under CR is linked to lifespan shortening in the non-obese. For example, in non-obese mice, CR-induced fat loss is inversely correlated with lifespan.33 In addition, age-associated pathologies such as respiratory disease correlated with body weight loss in non-obese humans although CR can lower biomarkers for cardiovascular disease in this segment of the population.34-36 Although losing body weight appears to lower lifespan in non-obese humans aged 50–70 even when health status is considered, it is unclear if this applies to other age cohorts.34-36 Together, these studies and rationales suggest that the starting weight of an individual may dictate whether CR-induced fat loss positively or negatively impacts lifespan. [...]

 

Nutrient Balance Affects the Response to CR

 

[...] Studies conducted in both flies and mice lend support to this notion. The fruit fly D. melanogaster can be subjected to a yeast-based or sugar-based diet. Decreased intake of yeast or sugar increases lifespan.39 Interestingly, the positive effect on lifespan per calorie decreased was much more substantial under the yeast-based diet relative to the sugar-based counterpart.39 This suggests that it is not simply the decreased caloric content per se that solely impacts lifespan. One possibility is that restriction of yeast-based diets also limits the amount of other nutrients within this diet. Consistent with this reasoning, methionine restriction significantly increases murine lifespan independently of caloric content.40,41 It is conceivable that the restriction of several amino-acids or nutrients would have similar effects. Therefore, in addition to altering overall caloric intake, certain CR diets may also extend lifespan via restriction of various lifespan-limiting dietary components or nutrients.

 

Specific nutritional composition may also explain contradictory results on the impact of different CR diets on lifespan. For example, one of many possible explanations for these apparently contradictory results on the effect of CR on rhesus monkey lifespan may be the dietary composition; the study in which the monkeys responded to CR had AL diets with higher sucrose and lower antioxidants and omega 3 polyunsaturated acids.7,42 Not surprisingly, these data imply that different nutrients may promote or limit lifespan. Thus, different CR regimens with multiple variations in overall nutrient balance are very likely to trigger a wide range of responses with respect to lifespan. For example, a CR regimen that restricts methionine while maintaining antioxidants might extend lifespan while a regimen that limits omega-3-polyunsaturated acids while maintaining sucrose may shorten lifespan. [...]

 

 

 

[Michael]

I thought this was a nice review. The full text is available.

Nucleus. 2014 Jan-Feb;5(1):56-65.
The fine line between lifespan extension and shortening in response to caloric restriction.
Szafranski K1, Mekhail K2.
 
...In stark contrast, CR fails to extend or even shortens lifespan in certain settings. CR-dependent lifespan shortening is linked to weight loss in the non-obese, mitochondrial hyperactivity, genomic inflexibility, and several other processes. Deciphering the balance between positive and negative effects of CR is critical to understanding its ultimate impact on aging....
PMID: 24637399

The bit about "CR-dependent lifespan shortening is linked to weight loss in the non-obese" is clearly nonsense: it is the methodological hallmark of properly-done CR studies that the researchers use nonobese controls.
 

Here are a few paragraphs...
 

Introduction

[...] However, contrary to the well-documented positive effects of caloric restriction, several studies reported caloric restriction to be neutral or even detrimental to lifespan. For example, studies have found that caloric restriction regimens fail to impact lifespan in rhesus monkeys,7 wild mice,8 medflies,9 an isolate of the nematode C. Remanai,10 the spider L. Hasselti,11 and some yeast strains.12,13 Even more striking, CR actually shortened lifespan in several models including houseflies,14 male butterflies,15 the rotifer Cephalodella sp.,16 ILSXISS mice strains,17,18 and some yeast strains (Table 1).13 The work done with ILSXISS mice is particularly poignant.

 

The question of whether CR extends lifespan in rhesus monkeys is still a very open one: the studies were methodologially weak and the results were frustratingly inconclusive.
 
The effects on wild mice have been oversimplified: the CR Society Archives are down just at the moment, but when they're up I'll direct all to my post, "Re: [CR] CR fails to increase AVG lifespan of genetically heterogenous wildtype mice due high early mortality", 2006/11/1.
 
I'm not too worried about CR's effects in non-mammalian species, or indeed the effects or lack of them of any particular putative anti-aging intervention; the fact that CR does work in most strains and subspecies of flies, nematodes, spiders, rotifers, and yeast as well as mice, rodents, apparently dogs, and possibly even rabbits and cattle, and shows very favorable effects in nonhuman primates, is powerful support for its translatability, but it would not be terribly worrisome if it only seemed to work in mammals and not in species that age radically differently from us.
 
Re: houseflies: The way that they impose CR upon flies is problematic for several reasons: this was explained in a post on the CR society list by none other than Michael Cooper, one of the investigators on the report of no LS extension in houseflies. See (once it's up again) the post "CR - Fruit Fly & House Fly (Drosophila and Musca Domestica)". 5 Aug 2005.
 

 

A meta-analysis of all mice studies excluding the ILSXISS strains reveals an average CR-dependent increase in lifespan of 15%.19 When the ILSXISS strains are included in the meta-analysis the average increase in lifespan drops to 2.9%.19 The ILSXISS studies set CR at 60% of AL intake in agreement with common standards in the field but it remains possible that more or less substantial restrictions may promote the lifespan of both ILSXISS and other mice strains. Taken together, these studies indicate that standard caloric restriction regimens do not universally promote longevity in various organisms. In other words, several more variables may exist within the equation determining the impact of CR on lifespan than originally anticipated. [...]

 

The ILSXISS crosses are enriched with genetics from the DBA/2 lab mouse strain, which is extremely sickly and responds poorly to CR, as discussed here in the context of another study using this strain.
 

 

Reduction of Body Weight under CR Can Positively or Negatively Affect Lifespan

[...] in obese human males, CR reduces body fat while also significantly decreasing obesity-related pathologies such as high blood pressure and chronic inflammation. ... CR-mediated weight loss is generally beneficial.

In contrast, fat loss under CR is linked to lifespan shortening in the non-obese. For example, in non-obese mice, CR-induced fat loss is inversely correlated with lifespan.

 

They're here eliding "Reduction of Body Weight" with "fat loss under CR," which are two different things — and also putting the latter point backward. Properly put, the point (which they're right about, and is a consistent finding by several groups) is that animals that maintain more of their fat mass (specifically) at a given level of CR respond better to CR.
 

 

In addition, age-associated pathologies such as respiratory disease correlated with body weight loss in non-obese humans although CR can lower biomarkers for cardiovascular disease in this segment of the population.34-36 Although losing body weight appears to lower lifespan in non-obese humans aged 50–70 even when health status is considered, it is unclear if this applies to other age cohorts.34-36 Together, these studies and rationales suggest that the starting weight of an individual may dictate whether CR-induced fat loss positively or negatively impacts lifespan. [...]

 

The studies they're quoting are not CR studies, but epidemiological studies of weight (or, more often, BMI) or weight loss in the general population. People's body weight and loss are dictated by many things, including thyroid hormone levels, non-exercise thermogenesis, brown fat levels, ambient temperature, smoking, and occult disease — and the degenerative aging process itself. The National Institute on Aging's Baltimore Longitudinal Study of Aging (BLSA), the "most comprehensive and longest running longitudinal examination of human aging in the world," has reported that
 

Approximately 9 years before death, the rate of weight loss increased to an average of 0.39 kg/year (P < 0.001) for all-cause mortality. For cancer deaths, weight loss accelerated significantly 3 years before death, regardless of age group. For cardiovascular deaths, the best-fitting inflection point increased with age, from 5 years for participants aged 60–69 years to 9–10 years before death for those aged 80 years or older. Results suggest that weight loss in older persons may begin earlier than previously believed. The duration of weight loss for noncancer deaths suggests that even distal changes in energy balance may be linked to risk of death.((1); my emphasis)
 

 
Predicted weight (in kilograms) by time to death and age at death for male decedents from the Baltimore Longitudinal Study of Aging, Maryland, 1958–2005. Participants who died at A) age 60–69 years (n = 87), B) age 70–79 years (n = 211), C) age 80–89 years (n = 320), D) age ≥90 years (n = 182). Refer to the Statistical Analysis portion of the text for a description of the models.(1)

 

Nearly no epidemiological studies on body weight/BMI have even run for long enough to account for a 9 year trajectory of disease-related weight loss. Most such studies either fail to exclude any early deaths that are likely related to undiagnosed disease onset, or exclude no more than 3 years of such deaths (I have never seen more than 5 years excluded). Aging itself is linked to unintended weight loss, as this graph from the Framingham Heart Study (2) shows:
 

 ▲ = Females; ◻ = Males
 

What's more informative is that both men and women who go on to be long-lived have lifelong trajectories of lower body weight than normally-lived people:
 

(Males)

 

(Females)

▲ = Long-lived (survived to age 80 for males and age 83 for females); ◻ = medium-lived (i.e., individuals whose age at death was between the ages of 65 and 80 for males and 65 and 83 for females). Also from the Framingham Heart Study (2).
 

Nutrient Balance Affects the Response to CR

 

This is true enough — but the examples they draw on here are again in invertebrates. The effects of different macronutrients in mammals are much less dramatic than they are in flies and yeast. Investigators have used a wide range of diets to successfully extend the lives of mice and rats, and — provided minimum adequate nutrition standards are met — they all work. The question is more a matter of what works best. I'm long on the record for changing my position on protein, for instance, and now support the guidance that to maximize CR benefits, younger people on CR should get the RDA of protein and not more; and the data on the DHA-accelerated aging hypothesis imply that people on CR should avoid long-chain polyunsaturated fatty acids (EPA, arachidonic acid, and especially DHA) in favor of the essential fatty acids per se (alpha-linolenic acid and linoleic acid (though less linoleic than the Standard American Diet).

 

References
1: Alley DE, Metter EJ, Griswold ME, Harris TB, Simonsick EM, Longo DL, Ferrucci L. Changes in weight at the end of life: characterizing weight loss by time to death in a cohort study of older men. Am J Epidemiol. 2010 Sep 1;172(5):558-65. doi: 10.1093/aje/kwq168. Epub 2010 Aug 2. PubMed PMID: 20682520; PubMed Central PMCID: PMC3025636.

2: Yashin AI, Akushevich IV, Arbeev KG, Akushevich L, Ukraintseva SV, Kulminski A. Insights on aging and exceptional longevity from longitudinal data: novel findings from the Framingham Heart Study. Age (Dordr). 2006 Dec;28(4):363-374. PubMed PMID: 17895962; PubMed Central PMCID: PMC1994150.

Edited by Michael, 25 January 2015 - 07:52 PM.