Beyond Calorie Restriction For Longevity: SENS And Other Strategies

Since the 1930s calorie restriction has been the gold standard for increasing lifespan in a variety of organisms ranging from worms to mice. The diet gained popularity in the 1980s when Roy Walford and Richard Weindruch managed to extend the lifespan of adult mice successfully for the first time [1]. And then later in 2004, Spindler and his group to extended both mean and maximum lifespan of mice when CR was initiated at 19 months of age, proving that it was never too late to benefit from CR if done properly [2, 3].

And while it was now proven that calorie restriction worked in mice and rats, giving us hope that we could extend our own lives using this simple dietary intervention, there was not much evidence that a sustained reduction in calories could slow down the rate of aging in humans.

In 2004, we saw the first results from a series of papers that were to be published showing that many of the benefits of CR we see in rodents also applied to humans.

Calorie restriction appeared to significantly reduce the risk of diabetes, heart disease, and stroke by inducing a highly favorable metabolic and lipid profile in humans practicing long-term CR. It was reported that the CR group had changes that mirrored CR animals with the exception of IGF-1, because it required a reduction in protein intake along with a reduction in calories.

Following on from this study, we saw further evidence for the benefits of CR in humans with people on the diet showing similar changes in thyroid hormones, core body temperature, sex hormones, and inflammatory markers that we see in animals, as well as skeletal muscle transcriptional profiles which demonstrated a shift towards a younger phenotype for people on CR.

Although the evidence is not conclusive that calorie restriction slows down biological aging and extends maximum lifespan in humans, there is evidence that CR can offer some protection against the most common age-related diseases we see in humans.

Beyond calorie restriction to improve health and lifespan

Calorie restriction seems to be one of the most logical and promising approaches to improving public health and possibly extending lifespan in humans, but it still remains unclear whether it’s practical, given that many people would struggle to adhere to such a strict diet.

There are also significant risks associated with practicing calorie restriction such as slower wound healing, increased risk of infection, lower bone density, and decreased muscle mass.

And it’s not clear who will derive the most benefits from the diet and how far one should go in restricting calories before there are negative consequences.

For example, it’s been shown in mice that the effect of 40% CR on lifespan can vary depending on genetics, with some strains of mice benefiting, while in others it has no effect or even shortens lifespan [5]. Mice who have the least reduction in body fat and body temperature in response to CR appear to have the greatest benefit from CR [6].

Conservation of fat mass may be important for the longevity of CR not only because it serves as an energy resource to help fight off infection, but as a major organ, it secretes many types of adipokines like Adiponectin, IL-6, TNF-α, among many others, which have important biological functions.

The inconsistency of calorie restriction to extend lifespan in model organisms, which includes the mixed results we see in rhesus monkeys subjected to CR, shows that we desperately need better ways at identifying who is responding positively or negatively to either dietary interventions or pharmaceutical drugs which target aging itself.

It’s currently not known how far one can restrict calories before being in danger of shortening their lifespan. Aside from the potential risks already mentioned with severe CR, free-living humans are exposed to many dangers that lab animals are not. That being said, even milder forms of calorie restriction may work just as well as 40% CR.

Still, it’s more practical to use CR mimetics in humans, and they could even be more effective without some of the side effects.

A more effective approach to improve public health and longevity

The insights we’ve learned by studying calorie restriction has been invaluable for longevity research. It not only showed us how malleable lifespan is, but it gave us clues regarding important pathways and genes that may be implicated in longevity. And some of these have resulted in the formation of companies’ which have been aiming to mimic the effects of calorie restriction with small molecules.

In the early 2000s, resveratrol was deemed a promising candidate for lifespan extension in humans because it was thought to activate sirtuins. A company named Sirtis was founded in 2004 by David Sinclair and Christoph Westphal, and eventually bought by GlaxoSmithKline for $720 Million, proving that there was significant interest in this area and companies recognized the potential of drugs which targeted aging.

Unfortunately, results in mice and humans using Sirtuin-activating compounds (STACs) which were developed by the company Sirtris never lived up to the hype and later the company was shut down. Nevertheless, the interest in intervening in aging to improve health and lifespan was growing significantly. And there are currently many on-going studies looking at STACs to treat a range of diseases from inflammatory conditions to metabolic disorders.

David Sinclair, the founder of Siritris, has since moved on from STACs based off the compound Resveratrol, such as SRT1720 and SRT2104, to more promising molecules known as NAD+ precursors like NMN.

It has been demonstrated in mice that the long-term administration of NMN is effective at mitigating many of the changes that occur with aging. These include improved energy metabolism, increased insulin sensitivity, and improvements in their lipid profile. NMN was also able to prevent the changes in gene expression that occur with aging in various tissues [4].

Given the promising results in multiple studies using NR and NMN, a study has been funded with the help of LEAF to test whether NMN is able to improve health and extend lifespan in healthy aged mice, as well as an inducible, accelerated-aging mouse model called “ICE”.

We are closer than ever to achieving significant lifespan extension

It’s an exciting time in the area of longevity research, where we might now be closer than ever in finding ways to intervene in the aging process and deliver effective therapies which may even reverse some of the hallmarks of aging.

Trials are currently underway in animals and humans which involve well-known compounds such as metformin, rapamycin, and NMN, all of which hold some promise in improving health and longevity. We also have multiple companies involved in the race to deliver senolytics for treating age-related disease and are part of the SENS strategy for comprehensive human rejuvenation.

There’s never been a more exciting time to get involved in the field of aging. If these treatments are proven effective, it will likely significantly increase investment and decrease the time it takes to reach ‘longevity escape velocity’, a term coined by Dr. Aubrey De Grey.

Watch Adam Ford’s interview with Dr. Aubrey De Grey about the progress of longevity research. Aubrey believes that we could be just three years away from robust mouse rejuvenation (RMR). This is a big deal because it will validate the SENS approach to longevity and very likely increase interest by the public and investment into the area of longevity research.

References

[1] Weindruch R, Walford RL.
Dietary restriction in mice beginning at 1 year of age: effect on life-span and
spontaneous cancer incidence

[2] Cao SX, Dhahbi JM, Mote PL, Spindler SR.
Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice.
PNAS 2001;98:10630–10635.

[3] Dhahbi JM, Kim H-J, Mote PL, Beaver RJ, Spindler SR.
The temporal linkage between the phenotypic and genomic responses to caloric restriction.
PNAS 2004;101:5524–5529

[4] Michael S. Bonkowski & David A. Sinclair
Slowing aging by design: the rise of NAD+ and sirtuin-activating compounds
Nature Reviews Molecular Cell Biology volume 17, pages 679–690 (2016)

[5] Chen-Yu Liao, Brad A. Rikke, Thomas E. Johnson, Vivian Diaz, and James F. Nelson
Genetic Variation in the Murine Lifespan Response to Dietary Restriction: from Life Extension to Life Shortening
Aging Cell. 2010 February ; 9(1): 92–95

[6] Liao CY, Rikke BA, Johnson TE, Gelfond JA, Diaz V, Nelson JF.
Fat maintenance is a predictor of the murine lifespan response to dietary restriction.
Aging Cell. 2011;10:629–639

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