Here's a short review of the effects of calorie restriction on two important areas in the science of metabolism and aging:

This review focuses on the emerging evidence that attenuation of the production of reactive oxygen species and inhibition of inflammatory pathways play a central role in the antiaging cardiovascular effects of caloric restriction. Particular emphasis is placed on the potential role of the plasma membrane redox system in caloric restriction-induced pathways responsible for sensing oxidative stress and increasing cellular oxidative stress resistance.

We propose that caloric restriction increases bioavailability of NO, decreases vascular reactive oxygen species generation, activates the Nrf2/antioxidant response element pathway, inducing reactive oxygen species detoxification systems, exerts antiinflammatory effects, and, thereby, suppresses initiation/progression of vascular disease that accompany aging.

Chronic inflammation and the generation of reactive oxygen species (or free radicals) are prominent in the present day view of how normal metabolic processes cause the accumulation of biochemical damage that is aging. Look back in the Fight Aging! archives for more:

• Inflammation and the Damage of Aging
• How Age-Damaged Mitochondria Cause Your Cells To Age-Damage You

Calorie restriction reduces the rate at which damage occurs in both of these noted avenues - fewer free radicals, more antioxidant biochemistry to soak up those free radicals, and less inflammation. Given that, it shouldn't be surprising to find that the practice of calorie restriction "makes everything better" when looking at the pace of age-related degeneration. Damage yourself more slowly and your health will last longer.

Beware of people bearing either / or choices, especially when both options are terrible. Nothing in life is binary, and there exist no inescapable boxes nor walls that cannot be torn down. You'll always find other choices, other paths forward, if you care to search hard enough.

Here is a charming either / or choice, posed by someone with surprisingly little vision for a medical research:

Controversially, Brown also suggests that wiping out cancer and heart disease might be misguided, because these are swifter, and therefore relatively desirable, ways to die. It would be easy to think him heartless, were it not for his moving and vivid descriptions in the book of watching his own father die from pancreatic cancer. Brown writes how he “returned one last time to the hospice on a vile rainy day - I hadn't seen him for a week - and it was like something from a horror movie. I had never seen someone so dead who was still alive.”

Brown admits “the experience of seeing my father in pain and being in a degraded state was very difficult. But, although it was awful, in the grander scheme, it was a relatively easy death. My father had expressed a fear of dying with dementia, and so that would have been much harder, and that's partly why I believe we shouldn't remove these acute forms of death (like cancer). We'll just be exposing ourselves to longer, more drawn-out forms of death.

It is utterly false to present a choice of working to prevent dementia or working to prevent cancer and heart disease. All can be done - there's no shortage of resources in the world. But this fellow is well with the cage of his preconceived limits: in his world, we must all suffer and die from some age-related disease. Not doing so isn't even a possibility. How odd to hear a researcher argue this point; one might almost think about pushing him back a century to argue about whether consumption or yellow fever is best to be adopted as the death of choice, and therefore no cures should be sought.

We live in an age on the verge of repairing the damage of aging, preventing all age-related disease, and extending the healthy human lifespan through other means besides. How can any medical researcher be debating which age-related degeneration should be left alone as the accepted mode of suffering and death? The strongest bars are found in the cages of the mind that we build for ourselves by accepting the world in its present form.

Ultimately, limits to action and endeavor - and in this case, limits to what can be achieved through medical research - stem from our preconceptions of what those limits should be. An incurable disease, known to all as a death sentence, is only an incurable disease until a group of vision raises the funds, performs the work, and develops a therapy. So too with age-related degeneration, suffering and death. One person's notion of the absolute wall to progress is a red flag to those more inclined to charge ahead and make progress happen.

The responsible practice of calorie restriction with optimal nutrition (CR) has nothing whatsoever to do with eating disorders like anorexia. The former is engaged methodically in order to meaningfully and measurably improve your health and longevity, while the latter is engaged carelessly and relentlessly in order to damage oneself, slaved to an impossible ideal.

There is a world of difference between those extremes. That is self-evident to anyone who's taken a serious shot at practicing CR for the health benefits, as well as anyone who's spent any time in the online or offline CR communities. But you'll always find some idiot - and some academic idiots in past years - who can't see eating in a more planned fashion as anything other than a mental illness, no matter how many facts to the contrary are right under their noses. CR practitioners need no help to send idiots packing, but it's nice to see that some of the folk involved in the ongoing CALERIE study of human CR recently published a more scholarly refutation than the idiots deserve.

Is caloric restriction associated with development of eating-disorder symptoms? Results from the CALERIE trial:

This study tested a secondary hypothesis of the CALERIE trial (Heilbronn et al., 2006) that a 12-month period of intentional dietary restriction would be associated with an increase in eating disorder symptoms.

...

All three dietary restriction arms were associated with increased dietary restraint and negative energy balance, but not with increased ED symptoms or other harmful psychological effects. Participants in the three calorie restriction arms lost significant amounts of body weight. The psychological and behavioral effects were maintained during a 6-month follow-up period. ... These results did not support the hypothesis that caloric restriction causes increased eating disorder symptoms in overweight adults. In general, caloric restriction had either benign or beneficial psychological and behavioral effects.

So hopefully we'll be hearing less of the anorexia association nonsense in the years ahead. People who exercise in a planned fashion so as to be healthy don't have to put up with nonsensical accusations of mental illness, so why should people who eat in a planned fashion so as to be healthy?

It was something like two years ago that I noted the pointlessness of trying to use the term "anti-aging" to describe longevity science or research into the repair of aging.

Unfortunately, some topics just can't be discussed well in email, blog and website; they are drowned out by the efforts of those trying to make money. So it is with scientific anti-aging research and the vast sea of static produced by the purveyors of useless, all brand and no cattle "anti-aging" products. Just take a look at what is seen when searching for any sane, non-monetary, responsible discussion of anti-aging science on Google, Google News, Google Blog Search and Technorati - a blizzard of junk and nonsense. It's the same everywhere you look, a storm of short-termist profit seeking that destroys the primary utility of the internet for these concepts, making it impossible for diverse groups to collaborate, exchange ideas and build new organizations as a part of a serious, ongoing cultural conversation on anti-aging science.

...

Anti-aging is beyond salvage as a term for discussion; we should move on and use other language to describe the technologies of healthy life extension and advanced medicine to extend healthy life spans.

But I'm stubborn, and so kept at it for a while, to see what the balance of voices looked like. Ultimately I took my own advice and moved on to terms like "repair of aging" and "longevity science." You need a bigger foghorn to compete with the folk presently engaged in efforts to define "anti-aging," either implicitly or explicitly. The term has solidly come to mean Revlon, skin cream, potions and the art of patching over the cracks so as to look younger, while doing absolutely nothing about the damage of aging. The forgery of the mirror and makeup, the magic show in which we expect to be entertained while understanding that none of it is real.

Oh well, move on. There is nothing to be gained by trying to talk to that marketplace by redefining "anti-aging" to mean serious longevity science. That is a hard path:

If there really was a significant spill-over of sentiment and support from consumers of "anti-aging" brands to meaningful, scientific anti-aging research - or even between different "anti-aging" brands in the marketplace - I don't think we'd be seeing quite the same sort of hostile confrontation between brand-holders and scientists as takes place today. More to the point, I suspect that volunteer organizations like the Methuselah Foundation would be having far less of an uphill struggle than has been the case to attain their present level of success, and scientists backing rapid progress towards working anti-aging therapies would not be struggling to raise large-scale funding and fight conservatism within their ranks.

The hundreds of thousands (millions?) of devoted purchasers of useless "anti-aging" products translates into very, very few people who understand and give support to serious attempts to repair the damage of aging through modern science. We advocates for longevity science may as well direct our educational and awareness efforts to the population at large - there is no special leverage to be had in speaking to Revlon customers. If there was, we'd have seen it already.

I've posted on RAGE before, a cell receptor structure that binds to a range of biochemicals, including the undesirable advanced glycation endproducts or AGEs (hence RAGE - receptor for AGEs). RAGE binds to other materials too, and presumably has an important role in the normal operation of your tissue, but the accumulation of AGEs with age turns it into a problem.

Problems caused - or not helped - by AGE buildup include kidney disease, and the many variations of blood pressure and heart conditions caused by a lack of elasticity in the tissues of heart and blood vessels. Diabetics in particular suffer due to more rapid accumulation of AGEs based on their metabolic biochemistry (e.g. high blood sugar, inflammation, free radicals).

At least some of the degenerations brought on by AGE buildup can be laid at the feet of the interaction with RAGE, and the resulting actions then taken by your cells. Cell receptors are like keyboards or buttons - hit them with the right sort of molecules and you're instructing the cell to take action. Here are a couple of papers on RAGE and age-related degeneration:

RAGE and its Ligands in Retinal Disease

Ligands for RAGE, in particular AGEs, have emerged as relevant to the pathogenesis of diabetic retinopathy and age-related macular disease. While the understanding of RAGE and its role in retinal dysfunction with aging, diabetes mellitus, and/or activation of pro-inflammatory pathways is less complete compared to other organ systems, increasing evidence indicates that RAGE can initiate and sustain significant cellular perturbations in the inner and outer retina. For these reasons, antagonism of RAGE interactions with its ligands may be a worthwhile therapeutic target in such seemingly disparate, visually threatening retinal diseases as diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinopathy.

Let's work out how to interfere in the reaction of AGEs with RAGE, in other words, as it looks like this will help prevent or slow the onset of common causes of age-related blindness. More of thes same in the next paper:

Receptor for Advanced Glycation Endproducts (RAGE): A Formidable Force in the Pathogenesis of the Cardiovascular Complications of Diabetes & Aging

Unifying mechanisms for the consequences of aging and chronic diabetes are coming to light with the identification that common to both settings is the production and accumulation of the largely irreversible Advanced Glycation Endproducts (AGEs). AGEs impart multiple consequences in the tissues; a key means by which they exert maladaptive effects is via their interaction with and activation of their chief cell surface receptor, Receptor for AGE or RAGE.

Although the time course, rate and extent of AGE generation and accumulation in diabetes and aging may be distinct, unifying outcomes of the ligand-RAGE interaction in the vasculature and heart are linked to upregulation of inflammatory and tissue-destructive mechanisms.

Consistent with these concepts, administration of the ligand-binding decoy of RAGE, soluble or sRAGE, suppresses early initiation and progression of atherosclerosis in diabetic mice; suppresses exaggerated neointimal expansion consequent to arterial injury; and mitigates the adverse impact of ischemia/reperfusion injury in the heart. Importantly, the RAGE ligand repertoire upregulated in these settings is not limited to AGEs. The key finding that RAGE was a multi-ligand receptor unified the concept that in diabetes and aging, innate and adaptive inflammatory mechanisms contribute to the pathogenesis of tissue injury.

We all know just how bad chronic inflammation is over the years, don't we?

All that excess fat hanging around over the years generates [inflammation which generates] atherosclerosis, which then kills you.

Now neutralizing the AGEs with another biochemical that prevents them from triggering cellular RAGE is a good plan - but a better plan is to break down the AGEs and remove them from the body. Various groups are working on that. The presence of AGEs is an important difference between young and old tissue, and we should be working to repair any such significant difference as a part of developing true rejuvenation medicine.