Poly-unsaturated fatty acids & Lifespan

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Poly-unsaturated fatty acids & Lifespan

Post by RRM »

Oxidative stress and life span
There are many types of oxidative stress, and all of them combined are considered just one part of aging and lifespan.

In rats, very high intakes of PUFAs (8% of diet in weight) do correspond to higher levels of lipid peroxidation, compared to high stearic acid (8%) intake.Csallany AS et al
One might expect that higher levels of PUFAs (relative to less vulnerable fatty acids) in tissues (heart mitochondria and microsomes) would correlate to lifespan,
but in birds no correlation was found between lifespan and natural PUFA levels.Gutiérrez AM et al

Comparing rats (max. lifespan 5 years) and pigeons (max. 35 years), membrane fatty acid composition of rats is more susceptible to damage (more PUFAs),
but no differences in levels of oxidative damage was found.Montgomery MK et al

There are various factors involved in total oxidative stress & lifespan.
Comparing the long-lived white-footed mouse (Peromyscus leucopus; max lifespan = 8 years) to the short-lived common laboratory mouse (Mus musculus C57BL/6J strain; max lifespan = 3.5 years);
1) Muscle mitochondria from the short-lived lab mouse produce more ROS (superoxide and hydrogen peroxide) than the white-footed mouse.
2) The activity of antioxidant enzymes superoxide dismutase 1, catalase and glutathione peroxidase 1 at young age is increased in the (long-lived) white-footed mouse.
3) The (long-lived) white-footed mouse displays lower levels of lipid peroxidation (ioprostanes) throughout life.
4) Though displaying higher levels of protein-derived carbonyls at young age, the age-dependent increase in protein-derived carbonyls is minimal in the (long-lived) white-footed mouse, in contrast to the linear increase in the (short-lived) common lab mouse. The much more pronounced age-dependent increase in protein-derived carbonyls in short-lived lab mouse supports enhanced protein homeostasis in long lived white-footed mouse.Shi Y et al

Particular long-lived mice (Insulin receptor substrate-1 null mice) demonstrate increased resistance to several age-related pathologies compared to wild type (WT) controls.
Of superoxide dismutases (SOD); glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT), and reduced glutathione (GHS), only hepatic CAT was significantly altered (increased) in these 'null' mice.
The levels of protein oxidation (protein carbonyl content) and lipid peroxidation (4-hydroxynonenal) were unaltered in 'null' mice,
although the hepatic GSH/GSSG ratio, indicating an oxidized environment, was significantly lower in long-lived 'null' mice. Page MM et al
What they didnt measure, was carbonyls from carbs, which could explain the discrepancy between GSH/GSSG ratio and protein oxidation plus lipid peroxidation.

Comparing long-lived parrots to short-lived quails;
"Only glutathione peroxidase was consistently higher in tissues of the long-living parrots and suggests higher protection against the harmful effects of hydroperoxides, which might be important for parrot longevity. The levels of oxidative damage were mostly statistically indistinguishable between parrots and quails (67%), occasionally higher (25%), but rarely lower (8%) in the parrots
The pronounced longevity of parrots appears to be independent of their antioxidant mechanisms and their accumulation of oxidative damage." Montgomery NK et al
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Birds vs mammals

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In this article they state: "Birds are unique because they combine a high rate of basal oxygen consumption with a high MLSP. Heart, brain, and lung mitochondrial ROS production and free radical leak (percent of total electron flow directed to ROS production) are lower in three species of birds of different orders than in mammals of similar body size and metabolic rate."
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Membrane composition and lifespan

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Membrane composition and lifespan

If membranes contain more PUFAs, this is associated with 'leakier' membranes and more active membrane pumps,
and thus with higher resting metabolic rate and shorter lifespan.
Membranes of birds contain less PUFAs when compared to mammals of the same size,
but similar % PUFAs compared to mammals with the same maximum longevity.Hulbert AJ
"cardiac death in man was accompanied by a high ratio of Arachidonic acid (20:4 n-6) relative to DHA (22:6 n-3)." Gudbjarnason S
"ALA-enriched diet prevents myocardial damage and expands longevity" Fiaccavento R et al

Membrane composition (% PUFA) does correlate with resting metabolic rate among species,
but resting metabolic rate within a species does not correlate with membrane fatty acid composition.Brzek P et al Haggerty C et al
Within species, membrane composition does correlate with lifespan, as within bees Haddad LS and wild mice Hulbert AJ
(queen bees are never allowed to eat pollen, high in PUFAs. worker bees develop 3-fold higher PUFAs in 1 week)

DHA-containing phospholipids represent 27-57% of all phospholipids in mice but only 2-6% in naked mole-rats (max lifespan > 28 yrs) Mitchell TW et al
Membrane composition from 42 mammalian species was determined. Max. lifespan indeed decreases as the ratio of n-3 to n-6 PUFAs increases.
In contrast to previous studies, however, we found no relation between lifespan and either membrane unsaturation (PUFAs) or DHA. Valencak TG et al
Within mammals, more lipid peroxidation resistant membranes are not the result of low PUFA content,
but mainly to shifting from DHA to LNA,
suggesting low delta6-desaturase activity in longevous animals .Pamplona R et al
"Membrane fatty acid composition appears to be a genetically-regulated parameter, specific for each particular species".
"Provided the diet is not deficient in polyunsaturated fat, it has minimal influence on a species’ membrane fatty acid composition and likely also on it’s maximum longevity."Hulbert AJ
Comparing various birds of different species, "a lack of correlation between the sensitivity to lipid peroxidation and body size or maximum life span was obtained" Gutiérrez AM

"In mice, dietary n-3 PUFA or n-6 PUFA -induced change in liver phospholipids did not affect lifespan" Valencak TG et al
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Membrane composition in long-lived human individuals

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Membrane composition in long-lived human individuals

Susceptibility to lipid peroxidation is partly genetic in origin.
heritability of longevity is 0.23 for females and 0.26 for males Herskin AM

Compared to other elderly, membranes from centenarians (> 100 yrs) showed:
1) decreased lipid peroxide levels and reduced susceptibility to peroxidation
2) increased unsaturated/saturated fatty acid ratio
3) higher levels of EPA and DHA, reduced LA and AA
4) higher fluidity
Membranes from centenarians show some distinct features in comparison with elderly subjects that might act in a protective way against injuries.Rabini RA et al

Nonagenarians; "higher concentration of PUFAs in LDL and alpha tocopherol in HDL might be parameters related to longevity" Solichova D
Nonagenarian (long-lived individuals) offspring had
1) significantly higher content of C16:1 n-7, trans C18:1 n-9, and total trans-fatty acids (trans fats may result from PUFA oxidation, serving as signalling molecules Goodfriend TL et al)
2) reduced content of LA (C18:2 n-6) and AA (C20:4 n-6).
3) No association was detected that could justify genetic predisposition for the increased trans C18:1 n-9, monounsaturated fatty acids and decreased omega-6 synthesis.
We concluded that erythrocyte membranes derived from nonagenarian offspring have a different lipid composition (reduced lipid peroxidation and increased membrane integrity) to that of the general population.Puca AA et al
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Increased unsaturated/saturated ratio

Post by overkees »

RRM wrote: 2) increased unsaturated/saturated fatty acid ratio
We should take into consideration here, that with aging this ratio always increases. Since centenarians are 100 years this would be a logical consequence. Or do I miss something?
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Re: increased unsaturated/saturated ratio

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overkees wrote:
RRM wrote:increased unsaturated/saturated fatty acid ratio
We should take into consideration here, that with aging this ratio always increases.
Not true.
Sure, several studies show "an age-related elevation in the unsaturation index of fatty acid profile" Hossain MS et al
and "increasing DHA and EPA (and decreasing AA) with age, independent of fatty acid intake" Otsuka R et al
but many others dont:

"changes in phospholipid class and fatty acid compositions with age are tissue-dependent"... "Heart mitochondrial membranes became more unsaturated with age"
... "The three main phospholipid classes in brain showed decreased omega-3, DHA (docosahexaenoic acid) and peroxidation index" Almaida-Pagán PF et al

"Age-related changes In the human red blood cell membrane: the level of PUFA decreased due to both omega-6 and omega-3 fractions as well as at the expense of their precursors. However, the decrease in the level of omega-3 fraction was more pronounced. As evidenced by a decrease in the content of unsaturated FA and PUFA in lipoproteins of both high and low density, the disturbance of PUFA transport by lipoproteins is one of the mechanisms of the decrease in PUFA level in the red blood cell membrane".Lishinevs'ka VIu

"Age-associated mitochondrial membrane changes include increases in omega-6 and decreases in omega-3" Pepe S

"Dietary supplementation normalised the age-related decrease in unsaturation index in cortical tissue in rats" Little SJ et al

"Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3:omega-6 PUFA imbalance" Pepe S

Bone marrow cell membranes of aged humans contain more glycerophospholipids containing arachidonic acid (AA; 20:4 n-6) than monounsaturated fatty acids,
and in the total fatty acid pool of the cells AA increased, which happened at the expense of omega-3 fatty acids, especially DHA (22:6 n-3). Kilpinen L et al

Advancing age is associated with increases in the levels of LA (18:2n6) and ALA (18:3n3) and a decrease in the levels of dihomo-gamma-linolenic acid (20:3n6) and EPA (20:5n3) of the plasma, liver, aorta, and renal artery in rats.Engler MM et al

"In mice, the age-related changes in fatty acid profile for microvessel membrane phosphoglycerides are reflected by increased saturation/unsaturation ratios and decreased unsaturation indices" Williams WM et al

"About 55% of the acyl groups of human vitreous are unsaturated fatty acids ... There are no significant changes between ages 37-82 years in the fatty acyl group content and composition of human vitreous" Reddy TS et al

"As mice aged, the hippocampus contained less DHA, though in the oldest age group, this DHA content was higher, accompanied with the highest vitamin E levels (preventing lipidoxidation) Petursdottir AL et al

"we have demonstrated an age-related increase in the concentration of interleukin-1beta increased lipid peroxidation in hippocampal tissue, which is accompanied by an age-related decrease in membrane arachidonic acid AA)." Murray CA et al

"the concentrations of both docosahexanoic acid (DHA) and arachidonic acid (AA), two main polyunsaturated fatty acids in neuronal membranes, were decreased in the hippocampus of aged rats, and were restored by dietary manipulation" Mc Gahon BM et al

"decreased level of total polyunsaturated fatty acids (PUFAs) in aging neuronal membrane" Yehuda S et al

"The age-related decrease in hippocampal membrane AA seems to be triggered by increased lipid peroxidation, which is involved with the decline of LTP" Amamoto T et al (LTP = long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously)

"impairments in long-term potentiation are associated with a decrease in membrane AA and DHA in aged rats; and treatment of aged rats with either of these polyunsaturated fatty acids (PUFAs) reverses age-related decrease in LTP and the decrease in membrane fatty acid concentration." ... "AA and DHA may be beneficial in preventing and/or improving age-related declines in brain and cardiovascular system function." Kiso Y et al
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Re: Poly-unsaturated fatty acids & Age

Post by overkees »

Well.. let's look at these researches too:

Proportion of individual fatty acids in the non-esterified (free) fatty acid (FFA) fraction in the serum of laboratory rats of different ages.
It was further demonstrated that the concentration of fatty acids with a very short chain fell significantly during development, so that C 8:0, for example, could be detected only in the first two age groups, but not in 14-day-old and adult rats. The concentration of the saturated fatty acids C 15:0 to C 18:0 in the serum FFA fraction showed a statistically significant increase, while the index expressing the ratio of saturated to unsaturated fatty acids displayed a downward trend during development.

Modulation of membrane phospholipid fatty acid composition by age and food restriction.
Phospholipids from liver mitochondrial and microsomal membrane preparations were analyzed to further assess the effects of age and lifelong calorie restriction on membrane lipid composition.
The data revealed characteristic patterns of age-related changes in ad libitum (AL) fed rats: membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively, while membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately 40%, and 22:5 content almost doubled making the peroxidizability index increase with age. In addition, levels of 16:1 and 18:1 decreased significantly with age, indicating a possible change in delta 9-desaturase activity coefficient.

Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake.
The fatty acid composition of the mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty acid was higher in the older group, although linoleic acid (18:2) was lower.

Anti-lipoperoxidation action of food restriction.
Chronic food restriction inhibited the age-related increase of malondialdehyde production and lipid hydroperoxides in liver mitochondrial and microsomal membranes. Restricting calories modified membrane fatty acid composition by increasing linoleic acid and decreasing docosapentaenoic acid content in both membranes.

Effects of dietary restriction on age-related changes in the phospholipid fatty acid composition of various rat tissues.
Saturated fatty acids (FAs) did not change significantly with age; mono- and bi-unsaturated FAs decreased in the liver and heart, and the ratio of the former to the latter increased in the liver, kidney and heart. PUFAs increased in the liver and heart.
The most abundant PUFAs, 20:4(n-6) and 22:6(n-3), either remained the same or increased with age.


Age-related accumulation of free polyunsaturated fatty acids in human retina.
There were significant correlations between age of the donors’ and the content of both free AA and DHA.
The present study provides the first evidence for the presence of FFAs in the human retina as well as an age-related accumulation of polyunsaturated fatty acids (PUFAs).
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Re: Poly-unsaturated fatty acids & Age

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So, we can still conclude that this is not true, right?
overkees wrote:We should take into consideration here, that with aging this ratio always increases
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Re: Poly-unsaturated fatty acids & Age

Post by overkees »

Yeah, I agree. That is not always and necessarily true.
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Poly-unsaturated fatty acids & Lifespan

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Also interesting:
“Therefore, the presence of relatively low degrees of fatty acid unsaturation is expected in the tissues of longevous animals. In agreement with this prediction, fatty acid analyses of heart phospholipids in eight mammals ranging in maximum life span (MLSP) from 3.5 to 46 years showed that their total number of double bonds is negatively correlated with MLSP (r = -0.78, P < 0.02). The low double content of longevous mammals was not due to a low polyunsaturated fatty acid content. Instead, it was mainly due to a redistribution between types of polyunsaturated fatty acids from the highly unsaturated docosahexaenoic acid (22:6n-3) to the less unsaturated linoleic acid (18:2n-6) in longevous animals

Or this:
This study shows that the fatty acid double bond content of both canary (MLSP = 24 years) and parakeet (MLSP = 21 years) hearts is intrinsically lower than in mouse (MLSP = 3.5 years) heart. This is caused by a redistribution between types of unsaturated fatty acids, mainly due to a lower content of the most highly unsaturated docosahexaenoic acid (22:6n-3) in the two birds in relation to the mammal.
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Poly-unsaturated fatty acids & Caloric restriction

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Calorie restriction and membrane fatty acid composition
Caloric restriction corresponds with increased longevity

Chronic food restriction inhibited the age-related increase of malondialdehyde production and lipid hydroperoxides.
The anti-lipoperoxidation action of food restriction could not be attributable to the changes in membrane lipid content nor vitamin E status.
Restricting calories modified membrane fatty acid composition by increasing ALA and decreasing DPA content in both membranes.Laganiere S et al

Caloric restriction was observed to increase the membrane content of C22:6 (DHA) and to decrease C18:2 (Linoleic acid; LA; omega-6) content. Celalu WT et al

(in dietary restricted rats) No statistically significant difference in the overall polyunsaturated fatty acid content was noted. Lee J et al

total number of fatty acid double bonds and the peroxidizability index were not changed by caloric restriction.
caloric restriction during 4 months decreases oxidative stress-derived damage to heart mitochondrial proteins,
due to an increase in the capacity of the restricted mitochondria to decompose oxidatively modified proteins. Pamplona R et al

With age, gondoic acid (20:1n-9) decreased in all organs, 14:1n-7 and vaccenic acid (18:1n-7) increased in the kidney and heart, oleic acid (18:1n-9) increased in the kidney; 20:2n-6, LA (18:2n-6) and DPA (22:5n-3) decreased in the liver and heart, DGLA (20:3n-6) decreased in the kidney and increased in the heart. The most abundant PUFAs, AA (20:4n-6) and DHA (22:6n-3), either remained the same or increased with age. Dietary restriction significantly counteracted most of these changes, but not all. DR magnified the increase in 20:2(n-6), for example, which may not be age-related. Tamborini I et al

Dietary restriction, which is known to retard various aging processes, was found to decrease the turnover rates of membrane lipid species. Consequently, the fatty acid composition in phospholipids remained unchanged in the synaptic plasma membranes of food restricted mice.Ando S et al

So, caloric restriction comes with less lipid peroxidation,
but not necessarily with less PUFAs.
Somehow, defense steps up its activities.
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Re: Poly-unsaturated fatty acids & Lifespan

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Dietary PUFA and lifespan

"The results show a beneficial effect of EPA and DHA on the life span of C. elegans" Hillyard SL et al

"ω-6 PUFAs activates autophagy, a cell recycling mechanism that promotes starvation survival and slows aging. Inactivation of C. elegans autophagy components reverses the increase in life span conferred by supplementing the C. elegans diet with these fasting-enriched ω-6 PUFAs." O'Rourke EJ
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Re: Poly-unsaturated fatty acids & Lifespan

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Why is there no conclusive correlation between membrane fatty acid profile and inter-specie lifespan?

Beecause we have been making a big mistake:
In nature, its is not about survival of the individual, but about survival of a specie.
Lifespan of a specie is hardly determined by chemistry (oxidation) versus biology (enzymatic defense),
but instead, by 'the blueprint' for each particular specie.
For specfic species its essential that individuals live long, medium or short lifes,
and this is reflected by their genetic make up, including the length of their telomeres,
determining actual lifespan of all organs.

We have been looking at it from an individual perspective; we as individuals want to live long(er),
so that is what we projected on various species. But a specie 'will prefer' a lifespan that fits the characteristics of that specie.
Longer living individuals may not fit the 'masterplan' for that specie.
So, the lifespan of a specie is determined by many factors, all included in its masterplan,
and certainly not exclusively determined by the fatty acid profile of its cell-membranes.
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Re: Poly-unsaturated fatty acids & Lifespan

Post by dime »

Spot on RRM.
I think the line about lifespan is drawn somewhere at the optimal point of wanting to live long and being in position to live long.
Pretty much every individual animal wants to live long (or maybe a better wording would be "doesn't want to die"), I think we can agree on this.
But most often this is limited by the environment, like predators, diet, climate, and million other factors.
Big guys, e.g. elephants, whales, and similar, have little danger from predators, so they do live pretty long. A small mouse is very likely to be eaten by the time it's 50 years old.. so mice mature and reproduce quickly. This is very simplistic though, just giving an example.

So lifespan (and your whole body) is optimized towards reproduction, which is what keeps species alive. It is not towards long life.
And this is not because your individual goal in life is to reproduce or keep the species alive, but simply because exactly when you reproduce is when the genetic material is passed on, thus driving the evolution of a specie.

I haven't investigated thoroughly, but I'm pretty sure that the age of reaching sexual maturation and lifespan (in relative terms) are well correlated between species, and even between human populations. People who live longer hit puberty later, than people who live shorter.
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Re: PUFAs and lifespan

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Dietary LCPUFAs highly inhibit delta 6 desaturase (in mice) and therefore inhibit AA generation Raz M, et al.
presence of a constitutively low delta6-desaturase activity in longevous animals Pamplona R, et al.
the nematode C. elegans ...produces a desaturase enzyme responsible for converting n-6 PUFA to the more peroxidation-prone n-3 PUFA. This enzyme is absent in higher animals.
Blocking this enzyme might result in a membrane composition with a reduced sensitivity to lipid peroxidation and consequently alter longevity. Hulbert, A.J. Although the effects observed were relatively modest, they were in the direction predicted if reduced FA chain length and desaturation both favor greater longevity. Shmookler Reis RJ, et al.

So, we can indeed say that the desaturase enzymes are important, but that a good defense system is also of great importance. So that if you ingest dietary DHA and EPA, there will still be lipid peroxidation due to their high suspectibility to oxidation, but there will also be a lot less pro inflammatory AA production and this might explain the longevity more than the lipid peroxidation. Also through other pathways, because the eicosanoids from EPA and DHA also have modulating effects on the AA eicosanoids.
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