22 Jun 2018 Aging, Metabolism, and Caloric Restriction
“Live fast and die young,” “the flame that burns twice as bright burns half as long,” “don’t burn the candle at both ends.”
These phrases embody the idea that our resources are limited, and the faster we use them the sooner they, and we, are gone.
For a while, a similar idea prevailed in biology and medicine that suggested that we would live longer if we reduced the amount of energy we produced and used, as is explained in this quote:
“The idea that aging should be linked to energy expenditure has a long history that can be traced to the late 1800s and the industrial revolution. Machines that are run fast wear out more quickly, so the notion was born that humans and animals might experience similar fates: the faster they live (expressed as greater energy expenditure), the sooner they die.” (1)
The rate of living theory was born out of this mechanical view of biology and states that the greater an organism’s energy expenditure, the shorter it’s lifespan. It has since been expanded to suggest that aging, health, and lifespan are tied to energy expenditure.
This theory has been primarily supported by the evidence that animals with lower metabolic rates relative to their body mass have longer lifespans and that low-calorie diets extend lifespan by reducing the metabolic rate. But, it turns out it’s not quite that simple.
Aging and Metabolism
The concept that animals with higher metabolic rates have shorter lives isn’t particularly noteworthy. It’s now common knowledge that small animals, like mice, typically have high metabolic rates (relative to their size) and short lifespans, while large animals, like elephants, typically have low metabolic rates (relative to their size) and long lifespans.
This finding that species’ metabolic rates correlate with their lifespans corroborated the rate of living theory. However, while it was originally assumed that the metabolic rate was responsible for the rate of aging, we’ve since learned that there are other factors that explain this finding (1, 2).
The most notable of these factors is the composition of the cellular and mitochondrial phospholipid membranes (3, 4) [Note: while there’s substantial evidence that these “membranes” may not exist, the same principle applies to the composition of the non-membrane lipid structural components]. These membranes play a vital role in the production and usage of energy.
The fatty acids that make up these membranes vary in terms of their saturation. The more saturated the fatty acids are, the more structurally stable they are. Weaker, more unsaturated membranes are more susceptible to damage and have a higher permeability to protons and ions (3, 4, 5).
When the fatty acids in these membranes become damaged, they increase oxidative stress which damages all parts of our cells, including their protein structure, fatty acids, and DNA (3). This impairs energy production and requires energy for repair, making it doubly wasteful.
And, the increased permeability to protons and ions reduces the production of usable energy and increases the production of heat, which effectively reduces the efficiency of energy production (5). The increased permeability also increases the activity of Na+/K+ ATPase and proton pumps, which increases the energy demand (5) [Note: while there’s substantial evidence that these “pumps” may not exist, the same principle of an increased energy demand still applies].
Together, the differences in oxidative damage, wasting of energy, and efficiency of energy production due to differences in membrane saturation account for the differences in metabolic rates between species as well as the differences in aging and lifespan (3, 4).
In other words, species that have more saturated membranes are more energetically efficient and this results in slower aging.
And, what’s even more remarkable is that within species, where the membrane saturation is typically constant, those with the highest metabolic rates relative to their body weight actually live the longest (1, 2, 3). This supports the directly opposite conclusion of the rate of living theory: producing and using more energy slows aging and extends lifespan.
Aging and Caloric Restriction
Now, what about all those caloric restriction studies that show that eating less reduces the metabolic rate and increases lifespan?
While reducing caloric intake has been shown to reliably increase lifespan while also slowing the metabolic rate, there’s now considerable evidence that factors other than the reduction in metabolic rate are responsible for the life-extending effects of these calorie-restricting-diets.
Firstly, these caloric restriction studies are often performed by splitting the subjects into a caloric restriction group and a control group that eats ad-libitum (meaning they can eat as much as they want). This presents a problem because the subjects fed ad-libitum become overweight and are prone to the early onset of diseases and death, making them poor controls.
In fact, the supposed life-extending effects of caloric restriction are directly related to weight gain in the ad-libitum control groups (6). In other words, the less weight gain there is in the control group, the less life-extending effects are seen in the caloric restriction group. This suggests that the “life-extending effects” seen in the caloric restriction groups are simply due to life-shortening effects of the control groups.
Secondly, caloric restriction inherently reduces the consumption of amino acids that have been shown to reduce longevity and increase oxidative damage, including methionine, cysteine, and tryptophan. It’s been shown that the life-extending effects of caloric restriction can be entirely accounted for by the reduction of these amino acids in the diet (7, 8, 9, 10).
In other words, simply reducing the consumption of these amino acids without reducing caloric intake results in the same life-extending effects. These effects on aging can at least partially be accounted for by changes in membrane saturation, which I explained earlier is the primary determinant of lifespan between species (8).
Lastly, caloric restriction also inherently reduces the consumption of polyunsaturated fatty acids (PUFA). PUFA consumption is also directly related to membrane unsaturation, which accounts for many of its effects on aging, health, and lifespan. (I’ve written about PUFA’s negative effects on energy balance here and here.)
So, while it hasn’t been directly studied in this context, a reduction in PUFA consumption is likely another factor that accounts for the life-extending effects of caloric restriction.
All three of these factors are corroborated by other studies showing that reductions in the metabolic rate are not responsible for the life-extending effects of caloric restriction (11, 12) and that reductions in membrane unsaturation are (3, 13, 14, 15).
The More Energy The Better
Now that it’s known that a faster metabolic rate is not the cause of a shorter lifespan, the popular narrative can be flipped on its head: running the human “machine” faster does not cause it to deteriorate quicker. Instead, the opposite is true.
As I’ve outlined in this article, energy is the driving force behind our health and all our bodily functions. From this bioenergetic view of health, it’s evident that the production of adequate amounts of energy is what allows for regeneration, rather than the deterioration and degeneration we see when energy production is impaired, such as in disease and aging.
Of course, this capacity for growth and regeneration isn’t compatible with a mechanical view of the human organism, further illustrating one of its many flaws.
As I’ve mentioned before, improving energy production is much easier said than done, as this process can be inhibited by various factors. I outline several of the key factors affecting energy production and usage, how they affect our health, and what you can do about them in my free health and energy balance mini-course, which you can sign up for below.
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- Speakman, John R. “Body size, energy metabolism and” The Journal of experimental biology, vol. 208, Pt 9, 2005, pp. 1717–30. doi:10.1242/jeb.01556.
- Hulbert, A. J. “On the importance of fatty acid composition of membranes for aging.” Journal of theoretical biology, 234, no. 2, 2005, pp. 277–88. doi:10.1016/j.jtbi.2004.11.024.
- Hulbert, A. J. “The links between membrane composition, metabolic rate and” Comparative biochemistry and physiology. Part A, Molecular & integrative physiology, vol. 150, no. 2, 2008, pp. 196–203. doi:10.1016/j.cbpa.2006.05.014.
- Seebacher, Frank, et al. “Plasticity of oxidative metabolism in variable climates: Molecular mechanisms.” Physiological and biochemical zoology : PBZ, 83, no. 5, 2010, pp. 721–32. doi:10.1086/649964.
- Sohal, Rajindar S., and Michael J. Forster. “Caloric restriction and the aging process: A critique.” Free radical biology & medicine, 73, 2014, pp. 366–82. doi:10.1016/j.freeradbiomed.2014.05.015.
- Pamplona, Reinald, and Gustavo Barja. “Mitochondrial oxidative stress, aging and caloric restriction: The protein and methionine connection.” Biochimica et biophysica acta, 1757, 5-6, 2006, pp. 496–508. doi:10.1016/j.bbabio.2006.01.009.
- Sanz, Alberto, et al. “Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins.” FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 20, no. 8, 2006, pp. 1064–73. doi:10.1096/fj.05-5568com.
- Orentreich, N., et al. “Low methionine ingestion by rats extends life span.” The Journal of nutrition, 123, no. 2, 1993, pp. 269–74. doi:10.1093/jn/123.2.269.
- Zimmerman, J. “Nutritional control of aging.” Experimental Gerontology, 38, 1-2, 2003, pp. 47–52. doi:10.1016/S0531-5565(02)00149-3.
- Masoro, E. J., et al. “Action of food restriction in delaying the aging process.” Proceedings of the National Academy of Sciences of the United States of America, 79, no. 13, 1982, pp. 4239–41.
- Ferguson, Melissa, et al. “Effect of long-term caloric restriction on oxygen consumption and body temperature in two different strains of mice.” Mechanisms of ageing and development, 128, no. 10, 2007, pp. 539–45. doi:10.1016/j.mad.2007.07.005.
- Lee, J., et al. “Modulation of cardiac mitochondrial membrane fluidity by age and calorie intake.” Free radical biology & medicine, 26, 3-4, 1999, pp. 260–65.
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