Mitochondria Touch on All of the Present Methods of Slowing Aging
Read on the topic aging research and one will soon enough arrive at a consideration of mitochondria, their function and dysfunction. They are everywhere in the literature. These organelles are responsible for processing nutrients into chemical energy stores, and also play a role in a variety of important mechanisms in cell growth and cell death. They mediate many beneficial cellular responses to stress via generation of reactive oxygen species in greater or less amounts. Further, they are a primary target for the cellular maintenance processes of autophagy, as when mitochondria malfunction they can cause serious harm to a cell and its surroundings. That portfolio of functions and concerns is connected to all of the present methods of metabolic alteration shown to modestly slow aging in laboratory animals.
Most of these methods utilize the induction of stress response mechanisms, particular those involved in calorie restriction, the reduction of nutrient intake, which overlap with responses to exercise, to heat, to toxins, and to lack of oxygen. Altered mitochondrial function appears frequently as a central mediating mechanism. Calorie restriction itself appears to depend on increased levels of autophagy - and as soon as autophagy is involved one has to consider the reduction in mitochondrial breakage and dysfunction that results from more active mitochondrial quality control. It is even possible to tie mitochondria to the more recent efforts that depart from metabolic manipulation in order to produce rejuvenation through targeted destruction of senescent cells. Since senescent cells are primed to self-destruct, and since that process of self-destruction is mediated by mitochondria, the various pharmaceutical senolytic drug candidates target mitochondrial molecular machinery in order to force the issue.
How much of degenerative aging is mediated by mitochondria? Mitochondrial composition correlates well with species life span, suggesting importance, but that doesn't necessarily bear any relationship to the degree of harm done in any given species by the age-related failure of mitochondrial function, by the damage that accumulates in mitochondrial DNA. The only sure way to find out is to repair the damage, restore mitochondrial function, and watch what happens in a mouse study. Unfortunately, the research community is not yet capable of achieving that goal, though inroads have been made on the SENS approach of allotopic expression - copying mitochondrial DNA into the cell nucleus to prevent damage to mitochondrial genes from depriving mitochondria of necessary proteins.
Targeting Mitochondria to Counteract Age-Related Cellular Dysfunction
In a rapidly aging society, new treatment options for age-related disorders and diseases will be increasingly important. Consequently, in recent decades, research has focused heavily on the processes of aging to reveal potential targets for prolonging health and lifespan. Consistent with this, interventions such as caloric restriction (CR) or exercise, as well as pharmacological strategies have been well established to improve health and to slow down aging.
As adenosine triphosphate (ATP)-producing power plants of the cell, mitochondria are in a unique position to influence an organism's aging process. Recent reports suggest that mitochondrial function is linked to age-associated biphasic alterations in metabolic activity, including an increase and afterwards progressive decrease in mitochondrial function. In addition, the byproducts of mitochondrial respiration, reactive oxygen species (ROS), are key determinants in the initiation of cellular senescence when present in high concentrations. Moreover, changes in mitochondrial dynamics in fusion and fission, as well as alterations in the mitochondrial membrane potential have been reported to cause cellular dysfunctions during senescence. Consequently, it seems reasonable that life-prolonging interventions, such as CR or exercise, as well as various drugs, target mitochondria.
Notably, impaired mitochondrial functions are reported to cause accelerated aging that affects primarily organs with high levels of energy demand, such as the brain, the heart, the skeletal muscle, as well as liver and kidney. The critical role of mitochondria in these organs becomes clinically visible in the case of mitochondrial diseases that frequently affect organs with high energy demand. The link between mitochondrial dysfunction and age-related diseases is well-established for Alzheimer's disease, myocardial infarction, and sarcopenia.
The process of aging evokes various alterations in mitochondrial Ca2+ handling, mitochondrial respiration, mitochondrial structure, as well as in the mitochondrial genome, which are mutually interrelated to each other. Results from cell culture and animal experiments suggest enhanced mitochondrial activity in middle age, but a decline in old age. Initially, increased activity of mitochondria might compensate for the decreased mitochondrial efficiency that occurs during aging. However, this enhanced mitochondrial activity might harm the cell long-term, for instance, by increased ROS production, and might even further promote age-related cellular dysfunction. It is of major importance to further investigate the molecular processes behind the role of mitochondria in aging, as well as their potential to serve as targets for therapeutic interventions.
Hi there, just a 2 cent.
Considering brain neurons have upwards of 2 million mitochondrias, I believe mitochondrias are immensely underweighted in the regular aging process and the secondary pathological one. This is demonstrated with that study that shows that mitochondrial DNA composition alters maximum lifespan potential in many mammals of varying maximum lifespans.
This is the GC composition, guanine cytosine. It makes a lot of sense, guanine nucleosides are safeguards (they form G-Quads that stabilize DNA), while cytosine nucleosides control telomerase access and methylation (5-methylcytosine, the methylation controls DNA epigenetic clock but the cytosine participates in that as an integral part of the DNA epigenetic clock too). Of course much of this in the nucleus, but the mitochondrial DNA is affected in a similar way.
Plus, it was demonstrated that mitochondrial DNA 8-oxodG (8-oxodiguanosine) lesions is Causal and correlative of mammal MLSP in their brain, heart and liver. .And, guanosine is formed of Guanine plus a ribose (ribofuranoside). That shows that weakest link is found in the mtDNA. That, mitochondrial ROS emission rate dictates damage accrual and thus, MLSP.
And, that the main modifiers of that, are the mtROS emission itself, mitochondrial UCPs, ETC Complexes respiration OXPHOS function, ATP levels maintenance and mitochondrial redox. HSPs, DNA lesion excision enzymatic repair, autophagy and DNA epigenetic transcription drifting slowing are also secondary elements that are required as acting in concert for longevity possibility. But, as the study showed, mtDNA was crucial and 77% in weight in explanation of varying maximum lifespan potentials in mammals - the weakest link and most vulnerable point that contributes to the maximum longevity.of a mammal
Just a 2 cent.
Is there any indication that mitochondrial dysfunction plays a part in the accumulation of extracellular junk and of cross-links in the ECM? My impression is that these forms of damage will occur even when neighbouring cells are functioning well. And that consequently autophagy, occurring inside cells, does nothing to prevent these forms of aging.
I have seen a paper indicating that amyloid plaque in the brain flows in and out of cells, so poor cellular housekeeping may contribute to amyloid buildup outside of cells. But generally my impression is that glycation creates cross links and folds proteins to create extracellular junk in response to the inevitable presence of glucose in the blood stream and extracellular fluid, and there is little autophagy within cells can do to prevent this.
If you know of anything to the contrary please point me to it.
Hi Chris ! Just a 2 cent. I could not find much either, it is more the reverse
that is true. AGEs contribute to cell apoptosis via mitochondrial dysfunction causing mitochondrial membrane potential depolarization, which means excess mtROS, oxidative stress, ATP energy crisis - cell death.
As you said, the stronger element for AGEs formation are glycation and glycoxidation upon glucose exposure.
But, not the only ones, AGEs can form independently from glucose and have an unidentified source besides glucose or other sugars. This may be a genetic component controlling, in part, its accumulation. Failing mitos would, in theory, haste ECM deterioration for the worse because the cells (like fibroblasts) would incapable/dying and ECM scaffolding would be compromised. ECM modelling depends in part in cells function, because the cells are an integral part of its creation (besides extracellular enzymes, collagen synthesis, crosslinking, MMPs matrix metaloproteinases ECM degradation remodelling/turnover). Autophagy, as you said, being intracellular is without reach and impact on extracellular junk - it accumulates anyway. Only MMPs can degrade some of this, but many crosslinking and AGEs are irreversible permanent products that linger there like in a dump (such as glucosepane, CML, furosine, pentosidine, etc) and are never removed.
Just a 2 cent.
I think we can learn some longevity lessons from the bowhead whale, which can live up to 500 years. It thrives in cold waters where the mitochondria are protected by lower and more stable body temps. Moreover, these whales take in large quantities of the strongest and most effective antioxidant we know, which is antaxanthin from the krill oil produced by marine algae. These whales should be studied in more detail to determine just what factors are allowing these whales to live so long... it must have something to do with a highly protective mitochondrial system.
Hi Biotechy ! Absolutely. Just a 2 cent.
Bowhead whales are a great model for extreme lifespan research.
One study had done transcriptome inspection in several of the Bowhead whale's organs. It found that it had improved genes relating to underwater hypoxia tolerance (due to higher endothelial nitric oxide synthase eNOS activity which meant better vasodilation of its arterial vasculature under low O2, akin to Naked mole rats living in dark subterrain hypoxia although NMRs do not reach 211 years old like Bowhead whales do. They also found variants of SIR/DAF/FOXOs in them which means they had better genetic protection with improved insulin IGF control, despite their extreme amounts of fat blubber they were highlh insulin sensitive thus suffere no diabetes from their 10-20 tons of blubber (20,000 to 40,000 lbs of thick fat layers). It demonstrated that their slow metabolism, delayed slow growth to huge size, very late puberty/sexual reprod onset coupled with tons of excess fat was viable. Their system is capable of working around this problem and still be insulin sensitive. It's ironic because beluga whales which are truly dolphins family, not whales, had diabetic problems from excess fat and were insulin resistant.Demonstrating a problem in the glucose disposal, fat cumul, triglyceride conversion, glycogen stocking, SIR/DAF/FOXOs/IGF insulin signalling dysfunction. Bowhead whales ingest tons of cryptoxanthins, astaxanthins red pigments in pink krill as you said, and as such an added layer of antioxidative protection since astaxanthin is lipid labile and incorporated into the inner mitochondrial membrane, scavenring mtROS and lipid peroxides released from peroxidized PUFA fatty acids in the mitochondrial membrane phospholipids. Actually, what may be happening is the evolutionary trick, Bowhead whales have a special hydrogenation process happening in their gut/stomach/intestines. Namely, that their intestinal gut bacterial microflora is of the kind of bacterias who create lipid hydrogenation by converting the rich Polyunsaturated fatty acids from all the krill it ingests towards Saturated fatty acids production instead. The effect of this gut bacterial hydrogenation would be incorporation of large amounts of Saturated fatty acids in the Bowhead whales mitochondrial membrane phospholipids - the evolutionary trick through lipidome composition reordering to a saturated fatty acids content that is far less peroxidizable/the membrane becomes lipid peroxidation resistant which means a drastic reduction of PUFA content and PUFA peroxides that reach the mitochondrial DNA and damage it through formation of
8-oxodG lesions in the mtDNA. Extremely long-lived animals show a distinct reordering of their mitochondrial lipidome towards reduced polyunsaturation, because polyunsaturated fatty acids are orders of magnitude more susceptible to becoming peroxidized due to their chain length and double-content, which are peroxidized elements of polyunsaturated fatty acids. This is visible in naked mole rats whom have 10 times less DHA EPA PUFA in their mitochondrial membranes vs mice, effectively , naked mole rats live 10 times longer than mice. This excess of mitochondrial membrane phospholipids polyunsaturated fatty acids dramatically shortens lifespan by the overload of lipid peroxidization of these lipids fatty acids - this in turn completely fries the mtDNA closeby. And, as specified , mtDNA is weakest link and 10 times more vulnerable to oxidative lesions formation - it's why there is so much 8-oxodG forming in the mtDNA. And, you can just imagine what a high mtROS emission rate does to this - it's utter cataclysmic for the naked mtDNA that is grilled non-stop.
What's more, is that a Scandinavian 1970s research had shown that whale heart lipidome composition in its mitochondrias was equal to RMR (resting metabolic rate) and hBPM (heart beats per minute), and of course, the longest lived whales had the lowest RMR, slowest metabolic speed, and lowest mitochondrial heart PUFA content. Whales by their huge size benefit from slowed enzymatic kinetic, or rather inhibited lipidome activity: they have a reduction of desaturase and elongase enzymes activity. Fat mass/body size and mass affect lipid enzymal activity, bigger body means less activity. These mitochondrial lipidome enzymes are responsible for increased PUFA formation. So not only is there hydrogenation going on and lipid reordering, there is also delipidation of the causal PUFAs. So, it really is concentrated all in the mitochondrial surrounding.
There is more, but I'll stop there, these animals have not revealed all their secrets yet. The main point is how to
Build a therapy that targets these findings.
Just a 2 cent.