The Insulin/IGF-1 pathway is a key axis in the complex of longevity regulation and is of great interest in both aging research and therapy. At its heart is a paradox: it’s necessary for growth and development but also for aging and modulates lifespan across species. By balancing the demands of growth with cellular homeostasis the Insulin/IGF-1 pathway controls a wide range of biological processes: metabolism, stress resistance and cellular repair mechanisms.
The Insulin IGF-1 Pathway
One of the most popular pathways of longevity is the Insulin/IGF-1 Signaling Pathway (IIS).
- Insulin is the main storage hormone that directs nutrient partitioning and glycogen replenishment. It basically opens up the cells so they can store glucose into liver and muscle glycogen.
- Insulin-Like Growth Factor (IGF-1) or somatomedin C is an IGF-1 encoded human gene. It’s also known as the ‘sulphation factor’. IGF-1’s job is to grow and develop tissue.
IGF-1 works through the IGF-1 receptor (IGF-1R) which is similar to the insulin receptor.
IGF-1 is produced in the liver when stimulated by Human Growth Hormone (HGH). IGF binding protein (IGFBP) is a protein that carries IGF-1 around the body and is regulated by insulin.
How Does the Insulin/IGF-1 Pathway Affect Aging?
The Insulin and Insulin-Like Growth Factor-1 (IGF-1) signaling pathways control cell growth and development, but they also affect aging. These pathways dictate how cells use nutrients and regulate energy production. Interestingly, slowing down the activity of these pathways can increase the life span of some animals. This suggests that genetic variation occurring in these pathways affect aging and longevity more than any other genetic pathways.
Key Studies on Longevity and Insulin Signaling:
- Mutating Insulin-like Receptor (1993, Nematodes)
- An insulin-like receptor, named DAF-2, was mutated and repressed in the worms (nematodes). By doing this, the nematodes lived twice as long as normal. This effect required a second gene called DAF-16 to act with a transcription factor known as a FOXO.
- DAF-2 and DAF-16 Interaction
- So DAF-2 sends the PI-3 kinase signalling pathway, and this in turn shortens lifespan by activating insulin/IGF-1 signalling and phosphorylating and inactivating DAF-16. Overexpressing DAF-16 reverses the effect of DAF-2 loss, i.e. it extends lifespan.
- Impact of Reduced Glucose and Carbohydrate Intake (FOXO Activity)
- Depletion of glucose and carbohydrates activates FOXO due to the inhibition of insulin/IGF-1 signaling. Adding just 2% glucose to the diet of roundworms was shown to reduce lifespan by 20% in a study by Lee et al. was attributed to the inhibition of DAF-16/FOXO and heat shock factor HSF-1 activity.
- Insulin/IGF-1 Receptor Mutations (Fruit Flies)
- Fruit flies bearing a mutation that amplifies expression of an ant-diabetic gene called CHICO have shown the largest increase in lifespan so far seen in experiments using D. melanogaster. CHICO encodes a protein similar to the insulin receptor substrate (IRS)-like signaling protein and when the mutation was paired with a reduction in IIS activity the lifespan of the flies was increased by 85%. The individual components separately increased lifespan by 48%.
- Role of dFOXO Proteins
- dFOXO proteins are transcription factors that live longer. Signaling that controls lifespan feeds into and inhibits insulin signaling in the fat tissue (lipocytes) of Drosophila.
- Knocking Out the IGF-1 Receptor (Mice)
- Knocking out the IGF-1 receptor in mice makes them live 33% longer. Mice who lack the insulin receptor in fat tissue live 18% longer.
- Mutation of the Insulin-dependent AKT Ortholog SCH9 (Yeast)
- SCH9 if mutated 3 times the life span of yeast. Also SIR2 over expression increase life span. SIR2 is a component of insulin/IGF-1pathway in C. Elegans.
All these observations indicate that the insulin/IGF-1 system is a major regulator of the organism longevity controlling many downstream pathways. They differ between the species but their orthologues can be found in humans as well. We don’t have that many human observations that would display the same longevity benefit of limiting blood sugar and insulin. Lab animals are also living in a very controlled environment and we can’t tell what’s their subjective wellbeing like. The problem in humans is not to mimic the long livest yeast diet but rather find a way that help us to eat less without unsustainable restriction
How Do Sirtuins Extend Lifespan?
Sirtuins are proteins that sense the energy state of the cell and work with NAD+. Calorie restriction can increase sirtuin activity, DNA repair and cellular stress responses. These keep cells healthy longer and potentially longer life. Activating these proteins is a way to slow down aging.
Longevity Through Sirtuin Activation and Insulin/IGF-1 Signaling Regulation
The interplay between the insulin/IGF-1 pathway and sirtuins is key to understanding aging and development in lower organisms like Caenorhabditis elegans. Research shows that when nematodes are stressed they can live longer by entering the Dauer stage. This adaptive phase allows them to survive starvation and temperature extremes, a remarkable example of stress induced longevity.
The sirtuins, especially the Sir2 gene and its homologs in other species, play a big role in this. These proteins act as metabolic sensors and extend life by influencing energy use, DNA repair and stress resistance. For example overexpressing Sir2 in yeast increases lifespan by 50%, sirtuin modulation is anti-aging.
In humans and other species sirtuin activity can be optimised through various dietary and lifestyle interventions. Glucose restriction, caloric reduction and following proper moderate(not too much) a ketogenic diet increase sirtuin activity and overall metabolic health by increasing NAD+ levels which is needed for energy metabolism and DNA repair. Exercise and heat exposure (like sauna) also increase NAD+ synthesis and sirtuin function and fat oxidation and cellular repair.
Keeping a consistent circadian rhythm is also important for sirtuin activity overall metabolic health and longevity. Disruptions in circadian rhythm are linked to metabolic disorders and decreased sirtuin activity so we need to have a daily routine to optimise bodily functions and longevity.
Also managing oxidative stress and preventing chronic DNA damage is important for sirtuin activity. Acute stressors can be beneficial if followed by proper recovery but chronic oxidative stress can deplete NAD+ levels and impair mitochondrial function and the body’s ability to repair DNA and maintain cellular health.
This summary of sirtuin activation and insulin/IGF-1 signalling makes sense of the biology of aging and gives us practical ways to live longer and be healthier across all species.
Concluding Remarks: Synthesizing Knowledge from the Insulin/IGF-1 Pathway and Sirtuin Activation for Longevity
The insulin/IGF-1 pathway and sirtuin activation offer deep biological insights into aging and longevity. These highly conserved pathways are intimately intertwined and directly regulate lifespan in organisms as diverse as yeast, flies, and mammals. Based on the examination of genetic and biochemical mechanisms involved, researchers have uncovered interventions that may promote longevity and health.
Mutations and other alterations in the insulin/IGF-1 pathway have been found in studies of nematodes and fruit flies, showing that decreases in this signaling pathway can dramatically prolong lifespan. These results highlight the growth/longevity paradox, in which the same signaling pathways that promote early development can speed aging if they are not properly downregulated in later life. This knowledge offers a template for targeting these pathways therapeutically to slow aging and age-related diseases.
Sirtuins provide another mechanism of control over the aging process, acting as metabolic sensors to respond to environmental and internal energy challenges, allowing organisms to adapt to stressful conditions and preserve cellular integrity. The advantages of activating sirtuins via dietary and lifestyle interventions–including caloric restriction, ketogenic diets, and regular exercise—are studied across species, and their universal role in promoting longevity is apparent.
Yet, the conundrum for humans remains how to best translate these laboratory findings into sustainable strategies. Unlike the laboratory, human lifestyles are inherently multifactorial and complex. It is imperative that dietary, exercise, and circadian rhythm interventions, among others, are not only efficacious but also easily maintainable in the long term. These interventions should also improve quality of life, so that humans may enjoy healthy longevity.
As the detailed mechanisms of these pathways to longevity are further elucidated, it is apparent that a multifaceted approach–one involving dietary and lifestyle interventions, as well as possibly pharmacological ones–will likely be required to fully tap their benefits. The end aim is to empower individuals to enjoy extended healthy longevity, by not only slowing the onset of aging but also by ensuring that the additional years are spent in optimal health. This intersection of genetics, biochemistry, and lifestyle represents an exciting new field in the endeavor to understand and maybe someday master the aging process.