The search for a fountain of youth has bedeviled kings and alchemists for centuries. Around 80 years ago, Cornell University's Clive McCay discovered that restricting the caloric intake of rats increased their life span by up to 50 percent. Since that time there has been a lot of research, but few conclusions as to the reasons behind the life-extending effects of caloric restriction.
The brain has been shown to be highly sensitive to fluctuations in available energy through food intake. Calorie restriction attenuates the progression of Alzheimer's disease in mouse models, for example, while diet-induced obesity exacerbates symptoms. Conversely, recent findings from the National Institute on Aging suggest that accelerated brain aging, as seen in the premature-aging disease Cockayne syndrome, may be slowed through increased caloric and fat intake, while caloric restriction accelerates disease progression.
National Institute on Aging research fellow Morten Scheibye-Knudsen details his findings in a story appearing in The Scientist online and summarized below. Clearly, he concludes, caloric restriction is not universally beneficial. But by studying the influence of diet on aging in the brain, researchers have discovered a number of bioenergetic molecules and druggable targets that may serve as candidates for interventions to delay the onset of neurodegenerative disorders. Thus, while immortality remains a fantasy, living a longer healthy life may be an achievable goal.
Caloric restriction and health
Of the many benefits of caloric restriction, improved ability to maintain glucose homeostasis is probably the best established. Caloric restriction improves glucose tolerance, decreases insulin secretion from the pancreas, and increases insulin sensitivity in the peripheral tissues in model organisms as well as in humans. Not surprisingly, mice and humans on caloric restriction are also leaner, with reduced fat accumulation in the liver, resulting in a decreased risk of developing fatty liver disease. Markers of inflammation also decrease, and cardiovascular parameters such as blood pressure improve-effects that can also be explained by improved insulin signaling and glucose homeostasis.
In addition, calorie-restricted animals are smaller than their well-fed counterparts, perhaps corresponding to decreased cell proliferation, a phenomenon that occurs in response to energy deficits in both normal and cancer cells. Decreased cell proliferation may be important, since a cell can only undergo a finite number of divisions before it ceases to divide, a phenomenon called cellular senescence. In simple organisms such as yeast, two types of life span can be defined: a chronological life span, or the length of time a yeast cell can survive, and a replicative life span, or the number of cell divisions a yeast cell can undergo. Decreased cell proliferation also leads to slower division of stem cells, allowing these progenitor cell populations to supply the various cell types of the body for longer periods of time. This sparing of stem-cell pools could explain why dietary restriction is particularly effective in maintaining tissue homeostasis in rapidly proliferating tissues such as skin, hair, and bone marrow.
Neural tissues, such as the brain and spinal cord, have a limited capacity to rejuvenate themselves through stem-cell renewal, however, perhaps explaining why dietary restriction may not impact these areas of the body as much as others. To complicate matters, rodents and many other model organisms do not normally suffer from neurodegeneration, and a possible neuroprotective effect of caloric restriction therefore cannot be extrapolated from longevity studies interrogating dietary interventions in those models. In order to circumvent this problem, researchers are studying neurodegenerative and premature aging diseases in humans to understand the effect of diet on brain health and aging.
University of California, Los Angeles, researcher Roy Walford, a pioneer in the field of caloric restriction, felt so strongly about the benefits of this dietary intervention that he even practiced a version of it himself, convinced that it would allow him to live to age 120. Nevertheless, he was diagnosed with amyotrophic lateral sclerosis (ALS), a rapidly progressing neurodegenerative disorder, and died in 2004 at age 79. It is now relatively well established that caloric restriction exacerbates the progression of ALS, while increasing caloric intake attenuates the disease. This may reflect an increase in basal energy consumption in ALS patients. Indeed, a recent study suggests that ALS patients can ingest a high-calorie diet without developing diseases such as obesity and diabetes. Unfortunately, the increased catabolism, in combination with progressive feeding difficulties, leads to significant weight loss in ALS patients.
These observations suggest that caloric intake can profoundly alter neurological health, supporting the idea that the human brain may be particularly sensitive to alterations in energy homeostasis. This sensitivity may stem from the organ's remarkably high metabolism: under resting conditions, the brain consumes roughly 20 percent of total body energy production, despite constituting only a minute fraction of body weight. In addition, the brain does not store energy as glycogen or fats as other organs do. In fact, the nervous system is largely unable to metabolize fatty acids for energy. Thus, the brain is highly dependent on glucose as a fuel source. Likely due to this strong glucose requirement for normal brain function, the majority of glucose uptake in the brain is insulin independent. Insulin increases brain glucose uptake by 10 to 20 percent, however, and central insulin resistance, which may occur in type-2 diabetes, decreases this insulin-stimulated glucose uptake.
As an alternative to glucose, the brain can draw energy from ketones, a group of metabolites synthesized from fatty acids in the liver. Interestingly, the addition of ketones as an alternative fuel source for the brain attenuates the progression of Alzheimer's in a mouse model of the disease. In contrast, fatty-acid ingestion is associated with the development of the disease, though likely only in carriers of the APOE4 risk allele. The mechanism for this is not well understood but may involve the role of APOE4 in the transport of cholesterol in the blood. Increased ingestion of fat leads to increases in circulating cholesterol levels that may predispose individuals with APOE4 to atherosclerosis, which in the brain vasculature is an independent risk factor for the development of Alzheimer's. Notably, diabetes, which leads to widespread atherosclerosis, is also an Alzheimer's risk factor.
Although this is speculative, one could imagine a decrease in neuronal energetic availability, due to insulin resistance and atherosclerosis of the brain vasculature, being involved in the pathogenesis of Alzheimer's disease. Similarly, a failure to meet the neuronal energy requirement in ALS may lead to loss of motor neurons. Further evidence for the role of dysregulated energy homeostasis in the body's neurons comes from Huntington's disease, a neurodegenerative disorder characterized by loss of voluntary movements, dementia, and often psychiatric symptoms. Like ALS patients, those suffering from Huntington's commonly have increased basal metabolism and unexplained weight loss. Interestingly, feeding a ketogenic diet slows disease progression in mouse models of both ALS and Huntington's diseases. And in Parkinson's patients, who also tend to show increased energy expenditure and weight loss, a ketogenic diet has likewise shown promising results.
It is clear that certain age-associated disorders such as Alzheimer's, Parkinson's, Huntington's, and ALS appear to be influenced by dietary energy intake. Nevertheless, little is known about how normal brain aging is modulated by dietary changes. Because many model systems, including rodents, do not naturally develop neurodegeneration, this has been a particularly challenging problem to address.
Although a wealth of knowledge regarding interventions in specific age-associated diseases such as Alzheimer's and Parkinson's diseases have been reported, little is known about interventions that may modulate normal brain aging. We are, however, getting closer to an understanding of fundamental aspects of neurological aging, and we may soon be able to intervene in the aging process as a whole, perhaps with the benefit of preventing Alzheimer's, Parkinson's, and other age-associated neurological diseases. Increasing the level of circulating ketones, through dietary interventions or exogenous ketone sources, may be one relatively easy way to intervene, and could be efficacious either alone or in combination with other targeted interventions. Further studies are needed to understand the optimal dietary regimens and supplements, but there are grounds for optimism.
(Source: The Scientist)