It’s fifty years since I completed my PhD on the biochemistry of mitochondrial aging. At that time, interest in the subject of aging was minimal. Fast forward to today and the biochemistry of aging and the role of mitochondria is centre stage. One can feel the breakthroughs coming very swiftly as pennies are dropping.
In the 1970’s, the centrality of mitochondria in the process of aging was based on a very simple premise: in senescence you run out of energy and it’s mitochondrial bioenergetics that generate that energy. Mitochondrial dysfunction in aged cells reduces the availability of chemical energy changes (Gibbs energy (∆G)), which means that the low entropic state that is a healthy living cell gradually increases until it fails.
Today, the fundamental truth above is fully appreciated
and can be integrated with many of the puzzles of aging..
Fifty years of results from genetic activity (genomics) ,
free radical theories of aging and metabolic signalling
can be reconciled into a bigger picture.
In addition, the disparate macro effects of obesity,
lifestyle, and diet on aging now all slot into place.
The key link is the new darling of the anti-aging world
… NAD+ and its aging-linked nemesis NADH + H+.
It’ll be tricky to explain in readable prose, but I will try.
The small molecule NAD+ decreases within cells with age. It is the oxidised form of a class of molecules called nucleotides. NAD+ is used up, consumed, in various biochemical processes and with age decreases despite being synthesised from scratch and carefully scavenged and recycled. It is also not easily supplemented.
The important thing about NAD+ is that it is able to accept electrons from hydrogen (H). These electrons come from the metabolism of food such as fats, proteins and sugars. NAD+ then becomes NADH + H+ and this molecule feeds electrons into the mitochondrion’s complex system of enzymes to produce chemical energy. It’s the ratio of NADH/NAD which is creating excitement in the aging world. Basically if NADH is much higher than NAD, ie the ratio is bigger than it should be, this is a very bad thing in terms of aging.
The reason why a high NADH/NAD is bad is because the mitochondria, unless very active energetically, cannot handle the amount of electrons that can be provided by excess NADH. Long story short, depending on how much the oversupply of electrons is, a burst of highly damaging free radicals is produced. Reactive oxygen species (ROS) as they are properly called, are known to increase with age and to be responsible for a lot of the cellular damage associated with aging. And, as is well known, we are urged to eat healthy foods high in anti-oxidants to prevent such damage.
Clearly then, since NAD+ reduces with age any increase in the size of the pool of NADH will make things worse. This is where 21st Century humanity come unstuck.
It’s a fact: modern humans in the developed countries are largely physically inactive, well fed and graze feeders.
This means that they have no spare capacity to store dietary sugar as glycogen. Sugar which is not needed for activity, cannot be stored because the stores are already full. Modern diets high in glucose syrups, maltodextrins, lactose, fructose and potato starch are effectively diets of sugar. The sugars must be metabolised within cells. They cannot hang around in the blood. The metabolised sugars are then either stored safely as fat or broken down further and their hydrogen passed to the mitochondria for oxidation. Here is the first source of hydrogen over supply together with the link to diet and obesity. Inactive bodies have inactive mitochondria. The stimulation of mitochondrial metabolic activity from baseline tickover is signalled in an array of ways, foremost amongst which is physical activity. The mitochondria are not ready to receive hydrogen/electrons, ie not powered up. They will however accept the electrons, but with accompanying disastrous free radical production as the electrons react in an uncontrolled way with oxygen. Here is the second driver of oversupply of hydrogen.
As a consequence of the above, ( viz UPF rich diets, grazing eating and sedentary living) the ratios of NADH to NAD become high; too high. This state risks massive spikes in free-radical damage which lead to premature aging and early cancers.
As I said at the start of this post, the biochemists now know what is going on. What will be the result? A new pill? Or a lifestyle change? Your guess, but at least we are close to knowing aging now.
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