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Deregulated Nutrient Sensing: Hallmark of Aging #5

Next in our hallmark of aging series is hallmark number 5, deregulated nutrient sensing. 

What is Nutrient Sensing?

There are many cues to tell us when we are hungry – it could be the growling and gurgling of the belly, feeling low energy, or even the ring of the lunch bell. On a cellular level, hunger is, in part, signaled by low levels of available glucose. This is called the insulin and IGF-1 signaling pathway.

The IIS Pathway

One of the most conserved aging-controlling pathways in evolution is the insulin and IGF-1 signaling pathway (IIS pathway), which participates in glucose and other nutrient sensing. It’s helpful to think of a pathway as a step-by-step process. In a simple example, A influences B, then B influences C. But, B can be acted on by factors outside of the pathway; this means that even if A influences B, B won’t influence C if that outside factor is there.

A ==> B ==> C

In the IIS pathway, A is growth hormone produced in the brain. B is insulin-like growth factor 1 or IGF-1 and is produced in response to growth hormone (A). And C, triggered first by IGF-1, is a variety of downstream actors that ultimately contribute to aging. The outside factor that acts on IGF-1 is nutrient restriction. That means, even in response to growth hormone, if the body is fasting, IGF-1 will not trigger the next step(s), C.

Slow Down to Slow Aging

In normal aging, growth hormone and IGF-1 levels decline and the pathway is decreased. But if the pathway is experimentally or artificially down regulated, then it extends longevity. This is thought to be true because the cells have lower rates of growth and metabolism and, as a result, lower rates of damage. Aged organisms also decrease IIS in an attempt to expand their lifespan. Defensive responses against aging, as seen in the other hallmarks, at a certain threshold can become negative and aggravate aging. There is always a sweet spot: you want to slow down the IIS pathway to prolong your healthspan, but not too much or for too long.

Nutrient Sensing: A Breakdown

It's time to examine the lumped “C” above, which includes a variety of downstream factors. The IIS pathway senses glucose, but downstream (C in the pathway shown above) includes three other nutrient-sensing systems: mTOR, which senses protein concentrations; AMPK and sirtuins, which detect low energy states by detecting high AMP and NAD+ levels, respectively.

mTOR plays a key role in regulating nearly all aspects of anabolic metabolism (the part of metabolism that constructs larger molecules from smaller parts and requires energy). Downregulating mTOR activity has been shown to extend longevity and increase heathspan.

Rapamycin, for example, a darling of the longevity world, has been shown to decrease mTOR activity and thereby increase longevity. mTOR activity has been shown to increase during aging in mouse hypothalamic (homeostasis regulating part of the brain) neurons and contribute to age-related obesity. This impact has been shown to be reversed by direct infusion of rapamycin to the hypothalamus. Of course, just like other parts of the IIS pathway, downregulating mTOR activity isn’t without undesirable side effects including impaired wound healing, insulin resistance, and cataracts.

The low-energy state sensors, AMPK and sirtuins, signal nutrient scarcity and catabolic metabolism (the part of metabolism that breaks down larger molecules into smaller parts). Upregulating these factors contribute to healthy aging. AMPK activation, for example, can even shut off mTORC1 (one of the complexes mTOR helps form) and may increase lifespan.

Nutrient Restriction by Intermittent Fasting

Nutrient restriction is one of the simplest ways to affect your rate of aging. As shown above, it limits the influence of IGF-1 (B above), AMPK, and sirtuins. Of course, you want to restrict food without malnourishment. One way to do this is by practicing intermittent fasting, which is a pattern of eating that switches from fasting to non-fasting periods. Unlike a food plan, it focuses on when to eat instead of what to eat. Although, some fasting plans consider both.

The concept of fasting has been around throughout human history, as hunter-gatherers had to spend long periods of time without nourishment when food was not readily available. Intermittent fasting replicates these “lean” periods as it focuses on voluntarily refraining from meals for a set period of time and eating during a set timeframe. This allows the body to conserve energy; less time is allocated for digestion and priority is given to other important processes, such as cell renewal. 

Popular fasting methods are outlined here. 

Additional Years and Benefits

In addition to increasing your healthspan, there are many benefits to intermittent fasting. In one study, non-obese, healthy adults who reduced their calorie intake by 15 to 25% for two years reported improved quality of life – including improved general health, sexual drive, and mood and reduced tension. They also lost an average of 7.6 kilograms of mostly body fat. Further findings from the trial also suggest improved resting metabolic rate and cognition. It may be worthwhile being a little bit hungry sometimes!

Written by: Katsume Stoneham, BS, Molecular Biology, MA, Public Health 

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