A venerable theory of aging is the Mitochondrial Free Radical Theory (MFRTA). Mitochondria are the energy factories of the cell, where sugar is burned to create electrochemical energy. Of necessity, the mitochondria use high-energy chemistry, and this creates toxic waste in the form of ROS–pieces of molecules that are too eager to combine with delicate biomolecules, turning useful compounds to toxic waste.
The MFR theory says that these ROS cause mutations in the DNA of the mitochondria that build up over time and cause the mitochondria to perform less well with age. Mitochondria are constantly turning over, that is, creating new mitochondria that inherit the mutations and accumulate new ones.
Over the years, this story has come apart. The key finding goes back to 1980 : mutations (for whatever reason) are not more severe in older people than in younger people. The mutations that appear in mitochondria with age are at a low level, and inconsistent with the assumed ROS mechanism .
But it remains undeniable that we have fewer mitochondria as we get older, and those we have become less efficient. Brain and muscle cells are the most energy intensive, and we have less energy for everything from running to thinking. Mitochondria are not the source of age-related decline; nevertheless maintaining (or restoring) mitochondrial health should be a part of any strategy to resist the ravages of age.
I recently became aware of this Nature paper from Japan: More important than genetic changes in old mitochondria are the epigenetic changes (changes in gene expression) that render them less efficient. Is there a way to restore the gene regulation in aging mitochondria to look more like the gene expression in energetic, young mitochondria?
“When glycine was added to culture media containing cells from the 97-year-old, the mitochondria in these cells became like new.” [quote from summary by PD Mangan]. Glycine is the simplest of the 20 amino acids that are building blocks of proteins in all eukaryotes. It is not classed as an “essential amino acid” because our bodies can manufacture glycine, but maybe we don’t make enough of it to maximize our lifespans.
The theory in the Japanese paper is that glycine treats the downstream symptom of epigenetic reprogramming in the mitochondria. In other words, glycine does not stop the detrimental epigenetic changes in mitochondria that come with age, however one of the most important of these changes results in a glycine shortage in the mitochondria. Hence, glycine supplementation effectively attacks the problem at an intermediate stage.
Could a molecule as simple (non-specific) as glycine be an anti-aging compound? Glycine comes to us with a sketchy but promising history. In one rat study, a hefty dose of glycine increased lifespan by 27% longer than controls. “Hefty” is the human equivalent of ~3 ounces per day. I’m tentatively filing this study in the “too good to be true” drawer, because it appeared only as a conference abstract 5 years ago and has never been fleshed out with a peer-reviewed full text.
A shortage of protein has a powerful anti-aging effect across many species. And a shortage of one critical amino acid–methionine–is sufficient to trigger this response. This may be because methionine is the “start codon”; every gene begins with a methionine, and a severe shortage of methionine can slow down all protein synthesis.
Directly engineering a shortage of methionine in the human body is just too difficult to manage, because too many protein foods have methionine, and we’re too fond of protein. (Animal proteins are consistently loaded with methionine, whereas some vegetable sources have less.) In studies of lab animals, a methionine shortage is engineered by using fully artificial protein sources, constituted from individual amino acids. People would never want to live this way on synthetic food, even if we could afford it; but using glycine to create a methionine shortage sounds more palatable. Glycine plays a role in breaking down methionine in the liver, and if the glycine level is jacked up super-high, it is (theoretically) possible to force this reaction so far as to create a methionine shortage.
For some of us, methionine restriction holds up the tantalizing prospect of gaining benefits of dietary restriction while allowing us to eat to satiety. But the idea remains untested in humans. Protein deficiency can lead to loss of strength and endurance and the ability to concentrate–even as it increases life expectancy. Depression is another risk. Rats that have tried methionine restriction are not recommending it for humans; in fact, they quickly come to crave methionine; they recognize methionine-deficient foods and shun them.
On the other hand, there are other diverse benefits documented for glycine supplementation, beginning with better sleep, insulin sensitivity and cancer resistance. A minimum of 3 or 4 grams is required to have any effect. You can buy it in powder form by the pound. From Finland, here’s Valdu Heiskanen’s comprehensive page on glycine.
Mitochondria have their own DNA
Hundreds (sometimes thousands) of mitochondria dot every cell in our bodies. They perform the task of burning sugar in a controlled process that captures most of the energy in electrochemical form (ATP) that is convenient for all the cell’s usage. In the deep evolutionary past, mitochondria were an invading bacteria, which gradually lost their virulence, then became domesticated in a symbiotic relationship, then fell into line doing the bidding of the cell nucleus (like other parts of the cell). But from that distant era they still retain a snippet of their own DNA–just 37 genes, all essential for the energy metabolism.
In the old MFR theory, mitochondria were thought to lose genetic integrity through mutations. In the new view, the genetic information isn’t lost, but the mitochondrial DNA is reprogrammed later in life, with the result that their performance suffers. Nominally, this is a promising finding; random mutations in a hundred trillion mitochondria would not be a feasible target for anti-aging interventions; but epigenetic reprogramming is presumably something the cell already knows how to do. The cell knows, but we don’t; our understanding of epigenetic markers and the way that they are programmed is still rudimentary (even in the nucleus, let alone the mitochondria). Our best hope for the near term would be if we don’t have to understand the process, because the nucleus takes care of the details. This brings us back to the general strategy of signaling to make each cell think it’s part of a young body.
How does PQQ work?
PGC-1a is a circulating hormone that says to the cell, “make more mitochondria.” You can’t take PGC-1a orally because it is a large protein molecule, and does not survive digestion. PQQ is a small molecule, more bioavailable when ingested, that increases circulating PGC-1a. The two-step process has been documented in rodents; oral PQQ leads to more mitochondria [ref, ref].
Does CoQ10 help?
CoQ10 (or ubiquinone) is essential to the metabolic function of mitochondria. Supplementation with CoQ10 has been found to enhance athletic stamina in most human studies [ref, ref, ref, exception]. This benefit is not to be sneered at, though it is unrelated to aging. Heart patients taking statin drugs have an induced deficiency in CoQ10, and need to take supplements. Other studies of CoQ10 suggest benefits for cardiovascular risk [ref] and for maintaining insulin sensitivity [ref]. On the negative side, CoQ10 cannot stimulate growth of new mitochondria, and rodent studies with CoQ10 have never demonstrated increased life span [ref, ref].
Exercise is the best thing we know for promoting replication of mitochondria. This has been substantiated in humans and in rodents. Exercise is a powerful stimulant for producing PGC-1a, and there are additional channels by which exercise promotes mitochondrial biogenesis, apart from PGC-1a [ref]. There is evidence for endurance exercise and interval training, but maybe not for strength training [another ref]. I was unable to find any direct comparison of the three.
Fasting and Ketogenic Diets
Fasting promotes mitochondrial biogenesis by a different pathway: AMPK [ref]. AMPK is expressed in response to a tight energy budget, but the AMPK response also decreases with age [ref]. Ketogenic diets (very low carb) also promote increases in mitochondria [in humans, in mice].
Chronic caloric restriction (as opposed to intermittent fasting) contributes to the health of mitochondria, but not to their number [ref].
The Bottom Line
Loss of Mitochondrial energy is connected to many of the deficits of old age; but most of the things you can do to improve mitochondrial function are the same things we do for a generalized anti-aging program. The new thing here is glycine. It’s $10 a pound and helps you sleep better.