An Example of Phospholipid and Lifespan Data

One of the lines of evidence that points to mitochondrial damage as an important contribution to degenerative aging is that the life spans of mammalian species correlate well with varying composition of mitochondrial membranes. Differences in composition produce membranes that have more or less resistance to oxidative damage, such as that caused as a side-effect of the processes taking place inside mitochondria when they generate energy store molecules to power other cellular mechanisms. The membrane pacemaker theory of aging is associated with these details.

Learning more about membrane composition and the fine details of how it interacts with damage processes will not tell us how to fix mitochondrial damage and thus greatly improve matters in aging by reversing its course, however. That is already known: the biotechnologies needed to repair mitochondria or work around the damage are established visions, under development in a preliminary fashion, and emerging from entirely separate fields of research. What we should take away from the work linked here is a sense that there are multiple areas of evidence to suggest that repairing damaged mitochondria throughout the body will be of significant benefit, a form of rejuvenation, and thus worthy of greater investment.

The maximal lifespan (MLS) of mammals is inversely correlated with the peroxidation index, a measure of the proportion and level of unsaturation of polyunsaturated fatty acids (PUFA) in membranes. This relationship is likely related to the fact that PUFA are highly susceptible to damage by peroxidation. Previous comparative work has examined membrane composition at the level of fatty acids, and relatively little is known regarding the distribution of PUFA across phospholipid classes or phospholipid molecules. In addition, data for humans is extremely rare in this area.

Here we present the first shotgun lipidomics analysis of mitochondrial membranes and the peroxidation index of skeletal muscle, liver, and brain in three mammals that span the range of mammalian longevity. The species compared were mice (MLS of 4 years), pigs (MLS of 27 years), and humans (MLS of 122 years). Mouse mitochondria contained highly unsaturated PUFA in all phospholipid classes. Human mitochondria had lower PUFA content and a lower degree of unsaturation of PUFA. Pig mitochondria shared characteristics of both mice and humans. We found that membrane susceptibility to peroxidation was primarily determined by a limited number of phospholipid molecules that differed between both tissues and species.



Obvious schoolboy question, but can you genetically engineer mice with low PUFA human like mitochondrial lipids, and if so, does this extend their lifespan?

Posted by: Jim at September 15th, 2015 8:28 AM

Second question - how does this observation fit into the SENS 'reductive hotspot' view of mitochondrial damage? If my understanding of the SENRF view is correct, the loss of mtDNA leads to mitochondria that lack damage to their membranes, enabling them to take over a cell, then export free radicals to the rest of the body. How would a mouse, with membranes more susceptible to damage wind up with a shorter lifespan? Under the SENS reductive hotspot view, surely these two variables should be uncorrelated?

I think Michael Rae replied in the past to tell me/others that perhaps mice have crappier respiratory processes to begin with.

Posted by: Jim at September 15th, 2015 8:38 AM

Hi Jim,

You could engineer such mice, but there are quite a few genes involved in determining membrane composition (multiple desaturases and elongases, phospholipase A2, and others), and I would expect that it would be virtually impossible to get a dose 'just right' to extend their lives, rather than undrdosing and gettiing no effect, or overdosing and killing them: although there are studies showing that the association between mitochondrial membrane unsaturation index and lifespan is still significant over and above the association with body size, the latter is the main reason small animals have highly unsaturated mt membranes: they need it to sustain their high metabolic activity per unit mass.

That said, there is plenty of experimental evidence supporting membrane unsturation as a driver of aging, such as (indirectly) that long-lived mice (CR or IGF-1 pathway mutations) have lower unsaturation indexes than ad lib-fed wild-type mice, and that feeding CR rodents a more unsaturated fat diet (extra soybean oil (over and above what's in the diet for EFA requirements) or fish oil) partly counteracts the effect of CR on mt membranes by overriding the metabolic control of desaturation of dietary fatty acids, and leads to shorter lives than the same CR animals with the same amount of extra fat from a less-unsturated source (lard and olive oil) (1), and cf. (2,5).

This fits in very nicely with Dr. de Grey's Mitochondrial Free Radical Theory of Aging (MiFRA), because peroxidizability rises exponentially with each double bond beyond the first within a fatty acyl moiety in a phospholipid, and the mitochondrial inner membrane is both 'ground zero' for ROS generation in vivo (it is the location within the mt of the electron transport chain) and is physically linked to the mitochondrial DNA, to which they can pass on free radical damage through propagation of lipid peroxidation, thus leading to increased mtDNA deletions, which are the drivers of aging via mitochondrial ROS generation in de Grey's MiFRA. Again, CR and IGF-1 mutations lower the age-related rise in mtDNA deletions, and feeding fats that are more unsaturated increases the burden of such deletions (1,3,4).

1. The Influence of Dietary Fat Source on Life Span in Calorie Restricted Mice.
López-Domínguez JA, Ramsey JJ, Tran D, Imai DM, Koehne A, Laing ST, Griffey SM, Kim K, Taylor SL, Hagopian K, Villalba JM, López-Lluch G, Navas P, McDonald RB.
J Gerontol A Biol Sci Med Sci. 2014 Oct 13. pii: glu177. [Epub ahead of print] PMID:25313149

2: Quiles JL, Ochoa JJ, Ramirez-Tortosa C, Battino M, Huertas JR, Martín Y, Mataix J. Dietary fat type (virgin olive vs. sunflower oils) affects age-related changes in DNA double-strand-breaks, antioxidant capacity and blood lipids in rats. Exp Gerontol. 2004 Aug;39(8):1189-98. PubMed PMID: 15288693.

3: Quiles JL, Ochoa JJ, Ramirez-Tortosa MC, Huertas JR, Mataix J. Age-related mitochondrial DNA deletion in rat liver depends on dietary fat unsaturation. J Gerontol A Biol Sci Med Sci. 2006 Feb;61(2):107-14. PubMed PMID: 16510854.

4: Ochoa JJ, Pamplona R, Ramirez-Tortosa MC, Granados-Principal S, Perez-Lopez P, Naudí A, Portero-Otin M, López-Frías M, Battino M, Quiles JL. Age-related changes in brain mitochondrial DNA deletion and oxidative stress are differentially modulated by dietary fat type and coenzyme Q₁₀. Free Radic Biol Med. 2011 May 1;50(9):1053-64. doi: 10.1016/j.freeradbiomed.2011.02.004. Epub 2011 Feb 16. PubMed PMID: 21335087.

5: Spindler SR, Mote PL, Flegal JM. Dietary supplementation with Lovaza and krill oil shortens the life span of long-lived F1 mice. Age (Dordr). 2014 Jun;36(3):9659. doi: 10.1007/s11357-014-9659-7. Epub 2014 May 10. PubMed PMID: 24816553; PubMed Central PMCID: PMC4082564.

Posted by: Michael at September 15th, 2015 11:05 AM

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