'Hallmarks of Aging' Series Part III: Nutrient Sensing, Mitochondrial Dysfunction, and Senescent Cells

Tackling the 3 "antagonistic" aging hallmarks.

Greetings!

Last week, I published part II in an ongoing series on the ‘Hallmarks of Aging.’¹

Hallmarks of Aging Series Part II: Epigenetics, Protein Homeostasis, and Autophagy

You can read part I here if you haven’t already.

Introducing the 'Hallmarks of Aging' Series

This week, we continue the series with a discussion of the 3 “antagonistic” hallmarks of aging: deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence.

Deregulated nutrient sensing: an overview 🍽️

Deregulated nutrient sensing is a hallmark of aging rooted in the altered functioning of the nutrient-sensing network.

The nutrient-sensing network's functions encompass autophagy, mRNA and ribosome biogenesis, protein synthesis, glucose, nucleotide, and lipid metabolism, mitochondrial biogenesis, and proteasomal activity. It adapts its activity based on nutritional and stress status, promoting anabolism (the building up of proteins and molecules) when nutrients are abundant and stress is low, or initiating cellular defense pathways in response to stress and nutrient scarcity.

Although the nutrient-sensing network plays a beneficial role in promoting anabolic processes during youth, its pro-aging properties become prominent in adulthood. The deregulation of this network is a significant contributor to the aging process.

What causes deregulated nutrient sensing?

The mechanisms of deregulated nutrient sensing involve disruptions in the IGF1 pathway and its associated signaling network. In humans, IGF1 levels peak during the second decade of life and then decline with age. Inhibition of the GH/IGF1 pathway during adulthood or late in life has been shown to extend the lifespan of various model organisms, including mice.

https://www.nature.com/articles/nrendo.2013.67

Human evidence suggests that low IGF1 levels in older women (≥ 95 years) and a mixed population of older adults correlate with a lower likelihood of cognitive impairment and death. High IGF-1 levels are positively correlated with age-related conditions such as dementia, diabetes, vascular disease, osteoporosis, and overall mortality.

Centenarians (people older than 100) show elevated concentrations of IGF1-binding proteins, indicating potential alterations in IGF1-related pathways in longevity. The possibility of developing antibodies or small molecules that selectively inhibit IGF1 receptor signaling, specifically targeting the somatotropic axis, could provide health benefits with manageable side effects.

Fixing deregulated nutrient sensing 🛠️ 

The most obvious factor in deregulated nutrient sensing — and the most obvious intervention — is nutrition.

Overnutrition triggers intracellular nutrient sensors like MTORC1, activated by amino acids, and the acetyltransferase EP300, activated by acetyl coenzyme; inhibits sensors that detect nutrient scarcity, such as AMP-activated kinase (AMPK) and deacetylases SIRT1 and SIRT3, which respond to NAD+ levels in the body; and represses catabolic reactions, suppressing adaptive cellular stress responses including autophagy, antioxidant defense, and DNA repair.

This may all sound paradoxical. Nutrient scarcity sounds like a bad thing, right? Chronic undernutrition is certainly a problem, but our body responds and adapts well to intermittent periods of nutrient scarcity, which is why interventions like fasting have good evidence to support their anti-aging effects.

Specifically, fasting and dietary restriction stimulate adaptive cellular stress responses while suppressing the somatotrophic axis, leading to lifespan extension in various model organisms — though more definitive evidence in humans is needed.

https://www.nejm.org/doi/full/10.1056/nejmra1905136 

In addition to fasting, ketogenic diets are approaches to modulate nutrient sensing and promote healthspan and lifespan.

Ketogenic diets increase ketone body production (e.g., 3-hydroxybutyrate) during fasting or carbohydrate restriction. Ketone bodies can replace glucose as a fuel in some cells/tissues and are associated with longevity benefits.

For example, permanent administration of 3-hydroxybutyrate increases lifespan and healthspan in mice, suggesting it mediates the beneficial effects of a ketogenic diet. Ketone bodies also have diverse effects, including vasodilatation, immune response activation, and inhibition of the NLRP3 inflammasome. The advent of exogenous ketone supplements makes it possible for humans to elevate ketone levels “artificially” (without dietary restriction) and thus, are an alluring but still-investigational avenue to healthy aging.

Additionally, drugs designed for conditions like cancer and metabolic diseases (e.g., rapamycin and metformin) often engage the nutrient-sensing network, making them candidates for repurposing as geroprotectors (“anti-aging” drugs).

Mitochondrial dysfunction: an overview 🪫🔋

Mitochondria, essential cell organelles, not only provide energy but also trigger inflammation and cell death when compromised.

Mitochondrial dysfunction during aging arises from various mechanisms, including mitochondrial DNA mutations, impaired proteostasis, reduced organelle turnover, and altered mitochondrial dynamics.