https://www.sciencedirect.com/science/article/abs/pii/S0304416509000385
In: Biology
The Caloric Restriction-induced life extension observation (I’m not sure it qualifies as a theory, more of a phenomenon) has been published back in 1935 by McCay et al. I mean frankly the paper you cited does a pretty good job capturing the history and the proposed mechanisms, so I’m not sure what you want me to explain. They go through the main hypotheses, their strengths and weaknesses, and then reach this conclusion:
> In the more than 65 years since the seminal publication of McCay
et al. [1], the mechanism underlying the life-prolonging and anti-
aging actions of CR has been sought. In spite of the many hypotheses
proposed and investigated, the mechanism remains unknown. During
most of the 20th century, the studied mechanisms involved specific
physiological processes, such as retardation of growth, decrease in fat
mass, and reduction of metabolic rate. These hypotheses had the
advantage of being testable with the intent to falsify. And indeed,
some have been falsified. Late in the 20th century, it was recognized
that uncovering the mechanisms underlying CR’s actions requires a
broader framework than hypotheses focused on a single process.
Hormesis was suggested as such a framework. The hormesis frame-
work has been a good first step, but it is now clear that it is also too
simple. Research in the 21st century has begun to provide insights
regarding the true complexity of CR’s mechanisms, including interac-
tions among mechanisms. The challenge is how to apply the basic approach of science of testing with intent to falsify to such a complex
system. This will require biologists with new skills and innovative
ways of exploring complex biological phenomena.
So it’s basically a multi faceted phenomenon, it is likely underlain by several mechanisms which themselves interact to manifest as even more mechanisms that, in the end, remain too complex for our pin-point approach to science. We need a paradigm shift in study approaches, and indeed this is happening. Early science focused on large scale approaches with a large scale read-out (remove an organ or put a lesion in it and see the effect on the organism as a whole with basic physiological parameters), then we moved on with the technological revolution to the cellular and then molecular approaches, where we target specific genes or biochemical pathways and observe cellular, histological, and global functional changes. And then we went even deeper to single cell and single molecule studies, and it seemed for a moment we’re about to go atomic, but all of a sudden data science came like a bulldozer where now we’re shifting to study molecular changes but at a very large scale (change something tiny and observe how every tiny thing we have changes then use computer science to understand what that even means). So it seems we’re on the right path, so perhaps in some decades we’ll have an answer.
But just so my comment isn’t all useless, I’ll mention some one or two prominent still-standing proposed mechanisms for CR with their juries still out:
The growth retardation mechanism and the reduction in basal metabolic rate mechanism both entail that caloric restriction puts a cap on metabolic rate, and that is thought to put less stress on the organism. For why that is, we need to invoke the attenuation of oxidative damage accumulation hypothesis: you see, our bodies are dynamic, metabolism is not as rigid as, get energy, use energy, too much energy, discard source/store energy. It’s more like the more energy you supply our system (in the chronic sense), the faster the rate of both anabolic (building) and catabolic (destroying) processes but in an asymmetrical manner, where the net result shifts to one side or other depending on many factors. And the issue is that when you breakdown any biofuel in our bodies, oxygen is inevitably involved, and oxygen is a double edged sword, it’s reactivity is great for carrying energy in some steps but also horrible because it disturbs things we like to keep stable. Oxygen reactions too often generate reactive oxygen species, which are highly reactive chemical moieties that can interact with DNA causing mutations or with proteins causing amino acid epimerization (mirroring their configuration) then misfolding ensues (then possibly aggregation and a whole constellation of sequelae). In highly replicative cells, DNA damage is bad, because it’s carried over. In highly quiescent cells (not much replication in genetically quiescent or not much activity in metabolically quiescent ones), misfolded proteins can accumulate because you can’t fix the epimerized amino acids and the cells are not active enough to have high flux of building blocks. So this altogether causes cumulative damage that over the years reduces cell function and impacts mostly those cells you can’t replace like neurons or might cause cancer in those that do replicate a lot (both happen in both but with different propensities). So these hypotheses are saying, you restrict caloric intake, you reduce metabolic rate, you reduce oxidative stress, you reduce the accumulated damage rate, you prolong life span by curbing aging instigators.
Then you got the recent hormesis hypothesis. Put simply, some things in low doses are good for you, but in high doses toxic. Of course now you’d think this is just “the dose makes the poison” approach, but that’s not quite it. It’s more about a biphasic response. For example, people who don’t exercise have high oxidative stress. People who exercise a LOT and intensely, also have high oxidative stress. But people who exercise moderately have low oxidative stress. So as you increases exercise intensity from zero, you don’t see a linear rise in bad effects, but rather a horizontal line with a dip in the middle. In the biological context of CR (historically, hormesis is more of a chemistry and toxicology term), it has been proposed that CR puts cells in a mild level of consistent stress, because of having to be economic with energy, and that this mild stress isn’t bad for the cells but rather good because it stimulates repair processes that then fix more problems preventing their accumulation. This has been supported by some studies, but unfortunately the idea is a bit broad and a little simplistic (but you never know, often times the simplest answer is the correct answer) so a lot remains to be discovered.
I hope I gave you enough information to understand this concept and if not, I urge you to read the paper you cited in depth, it’s quite good!
Edit: English
As I understand it the ‘miracle cure’ part of it is a thing called autophagy. That’s a little bit like the garbage trucks of your body, going round and taking away all of the damaged cells and general waste, off to the recycling plant. And the result is that you live better and longer with fewer damaged cells around screwing things up.
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