The insulin/IGF-1 pathway is a key player in how long organisms live. Here's what you need to know:
- What It Does: This pathway controls growth, metabolism, and how cells repair themselves. Lower activity in this pathway shifts the body’s focus from growth to repair, which can extend lifespan.
- Key Findings: In C. elegans (worms), mutations in this pathway can double lifespan. In humans, centenarians often show traits like low fasting insulin and better insulin sensitivity.
- How It Works: Reduced activity boosts stress resistance, activates cellular repair (like autophagy), and shifts metabolism from glucose to fat for energy.
- Applications: Caloric restriction, genetic insights (like FOXO3A), and potential drugs targeting this pathway are being explored to promote healthy aging.
This research shows how tweaking a single biological system can impact aging across species. Let’s explore how it works and its potential for human longevity.
The longevity advantage of genetic deficiencies in growth hormone/IGF-1 signaling | Valter Longo
Key Research Findings on Insulin/IGF-1 and Lifespan
Research spanning multiple species highlights a clear connection: reduced insulin/IGF-1 signaling (IIS) is linked to longer lifespans. Here's a breakdown of findings from studies on invertebrates, rodents, and humans.
Findings from Invertebrate Studies
In simple organisms, dialing down IIS has shown remarkable effects on lifespan. For example, in Caenorhabditis elegans, single mutations in IIS-related genes like daf-2 (analogous to the insulin/IGF-1 receptor) and age-1 (similar to PI3K) can double their lifespan[2]. These benefits rely on the activation of DAF-16, a transcription factor that boosts stress resistance and repair mechanisms[2].
Similarly, in Drosophila melanogaster (fruit flies), mutations in genes such as chico (an insulin receptor substrate) extend female lifespans by nearly 48%[2]. Other mutations affecting the insulin receptor (InR) further enhance longevity. An interesting example in C. elegans is the dauer larvae stage - a survival adaptation that allows these worms to live up to eight times longer under adverse conditions in lab settings[2]. These studies in invertebrates have laid the groundwork for exploring IIS in more complex organisms.
Evidence from Rodent Models
Rodent studies provide deeper insights into how IIS influences aging in mammals. Several dwarf mouse models, including Prop1df/df, Pit1dw/dw, GHRHRlit/lit, and GHR−/−, live longer lives, often accompanied by lower insulin and glucose levels and improved insulin sensitivity[1]. FIRKO mice, which lack insulin receptors in fat tissue, also show extended lifespans, reduced fat mass, and delayed age-related declines in insulin sensitivity[1].
The KLOTHO gene is another key player. Overexpressing KLOTHO reduces IIS and promotes longevity, while mutations in this gene accelerate aging[1]. Interestingly, some long-lived mice exhibit tissue-specific insulin resistance, suggesting that the intensity of insulin signaling in particular tissues might matter more than overall sensitivity[1]. These rodent models provide a nuanced view of how IIS affects aging and longevity.
Human Studies and Complexities
Human studies reveal a more intricate but consistent picture. Centenarians often share traits such as low fasting insulin, high insulin sensitivity, and specific IIS-related genetic variations (e.g., FOXO3A and the GHR exon 3 deletion)[5][6]. The FOXO3A gene stands out as one of the most replicated longevity genes.
Research on Ashkenazi Jewish centenarians adds another layer of complexity. Female offspring of these centenarians show 35% higher IGF-1 levels compared to controls, possibly compensating for reduced IGF-1 receptor activity. These women also tend to be shorter in stature[5]. Additionally, the d3/d3 genotype of the growth hormone receptor exon 3 deletion has been linked to an approximate 10-year increase in lifespan[5].
Diet also plays a role. Diets with high insulinemic potential - those that strongly stimulate insulin release - are associated with higher risks of mortality from all causes, including cardiovascular disease and cancer[6]. Caloric restriction, a well-known intervention, interacts with the IIS pathway but may only lower IGF-1 levels in humans if protein intake is reduced as well[5].
Interestingly, centenarians share metabolic characteristics with individuals on calorie-restricted diets. These include slower cell growth, a shift from cellular proliferation to repair, and fewer senescent cells. These adaptations appear to be influenced by the GH/IGF-1/insulin system[5]. Overall, human studies reinforce the idea that lower IGF-1 levels combined with enhanced insulin sensitivity contribute to better survival, mirroring findings across species.
How IIS Changes Promote Longevity
The insulin/IGF-1 signaling (IIS) pathway plays a key role in aging, and reducing its activity sets off a series of cellular and metabolic changes that can extend lifespan. When IIS activity decreases, the body shifts its focus from growth to repair, creating conditions that promote longevity.
Cellular Repair and Maintenance
Lower IIS activity encourages cells to prioritize repair mechanisms over growth. This shift activates key processes that help maintain cellular health and function.
One of the most important processes here is autophagy, a cellular recycling system. Normally, autophagy is suppressed by the PI3K/AKT/mTOR signaling pathway[7]. However, when IIS activity is reduced, autophagy ramps up. This allows cells to clear out damaged mitochondria and misfolded proteins, preventing the buildup of harmful cellular debris.
Research in WI-38 human diploid fibroblasts highlights the importance of autophagy. In these studies, IGF-1 signaling was found to inhibit autophagy, leading to an accumulation of dysfunctional mitochondria and a decline in long-term cell viability[7]. This shows how active IIS can accelerate aging by limiting cellular maintenance.
Reduced IIS also activates FOXO transcription factors, which enhance DNA repair and boost antioxidant defenses[8]. Improved DNA repair helps prevent the accumulation of genetic damage over time. As one study notes:
"These experiments provide one of the most persuasive arguments to date that senescence and the appearance of progeroid features result from active recognition and response to DNA damage, rather than passive damage accumulation."[8]
The effects of IIS on cellular repair also depend on external conditions. For example, during starvation, AMPK inhibits mTORC1 while insulin and IGF-1 signaling decreases, promoting autophagy[7]. On the other hand, when growth factors are plentiful, AKT activates mTORC1, suppressing these repair processes[7].
In addition to enhancing repair, reduced IIS reprograms cellular metabolism, further contributing to longevity.
Metabolic Changes That Support Longevity
Alongside improved repair mechanisms, reduced IIS triggers metabolic shifts that create a more resilient cellular environment, helping to extend lifespan. These changes reflect a fundamental reorganization of how cells produce and use energy.
FOXO transcription factors play a central role in adapting cells to nutrient scarcity and maintaining metabolic balance[2]. Under reduced IIS, FOXO promotes a shift from glucose metabolism to lipid oxidation, a more efficient energy process that generates fewer harmful byproducts.
Reduced IIS also boosts stress resistance, lowers inflammation, and supports mitochondrial biogenesis[1]. These changes make cells better equipped to handle environmental stressors and maintain their function over time.
Additionally, AMPK activation under reduced IIS increases NAD⁺ levels, activates SIRT1, and promotes mitochondrial biogenesis, creating a feedback loop that enhances stress resistance and energy production[9].
A key feature of this metabolic reprogramming is the shift from glycolytic metabolism (which relies on glucose) to oxidative metabolism (which relies on lipids). This pattern is consistently linked to improved healthspan across species and interventions[9].
Interestingly, these metabolic traits are often observed in naturally long-lived individuals. For instance, centenarians and their offspring tend to maintain glucose tolerance and insulin sensitivity, preserving the metabolic flexibility that supports longevity[2].
Together, these findings show how modulating IIS can initiate cellular repair and metabolic changes that contribute to a longer, healthier life. They also help explain why practices like caloric restriction and intermittent fasting - both of which reduce IIS activity - are associated with increased lifespan.
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Applications for Human Longevity Science
The research into the insulin/IGF-1 signaling (IIS) pathway has opened up exciting possibilities for extending human lifespan. While studies in animals have shown remarkable results in lifespan extension through IIS modulation, applying these findings to humans presents unique challenges. Here, we delve into how this science translates into lifestyle changes, genetic insights, and pharmacological advancements aimed at promoting longevity.
Interventions Targeting the Pathway
Efforts to harness the benefits of the IIS pathway for human longevity include lifestyle adjustments, genetic research, and cutting-edge pharmaceutical developments.
Caloric restriction has emerged as a well-documented method to reduce IIS activity. This dietary approach mimics the metabolic patterns observed in centenarians, preserving insulin sensitivity and maintaining lower blood glucose levels[4][1].
Genetic strategies are also gaining attention. Variations in IIS-related genes, such as FOXO3A, have been linked to enhanced survival rates[1][12]. For instance, the Leiden 85-plus Study revealed that women with specific genetic profiles involving the GHRHR, GH1, IGF-1, INS, and IRS1 genes experienced better survival rates and less cognitive decline into their nineties[1].
Pharmacological interventions hold significant promise. Research by Amgen Inc. and Albert Einstein College of Medicine demonstrated that administering the IGF-1R antibody L2-Cmu to 18-month-old female mice increased their median lifespan by 9% while reducing inflammation and tumor growth[10]. With IGF-1R monoclonal antibodies already available for human use, further exploration of their potential is warranted[10].
Interestingly, targeting IGF-1R signaling after developmental stages appears to offer longevity benefits while minimizing adverse effects[10]. These interventions often show sex-specific results, with women, particularly older women, benefiting more. For example, in female nonagenarians, lower IGF-1 levels have been associated with longer survival[11]. Similarly, studies in mice suggest that females derive greater lifespan benefits from IIS modulation compared to males[10].
Connection to MASI Longevity Science
These findings directly influence MASI Longevity Science's approach to supplements, focusing on supporting the downstream benefits of reduced IIS activity. While directly manipulating the IIS pathway in humans remains complex, certain compounds can enhance the positive effects associated with decreased IIS activity.
NMN (Nicotinamide Mononucleotide) plays a key role in maintaining cellular energy. Reduced IIS activity can activate AMPK, boosting NAD⁺ levels and triggering SIRT1 activation, which supports mitochondrial function. MASI's NMN formula provides the building blocks for NAD⁺ synthesis, promoting sustained energy production and better stress resilience.
Spermidine enhances autophagy, a process critical for cellular maintenance. By facilitating the removal of damaged cellular components, spermidine supports renewal and repair at the cellular level.
Resveratrol complements these metabolic shifts by activating SIRT1, working synergistically with increased NAD⁺ levels to improve metabolic flexibility and enhance stress resistance.
Fisetin contributes to cellular health by reducing inflammation, echoing the protective effects seen in studies targeting IGF-1R signaling.
MASI Longevity Science emphasizes a science-driven approach to healthy aging, leveraging supplements that address the cellular processes influenced by IIS. Manufactured in Germany and tested in Switzerland, MASI ensures its products meet rigorous standards for safety, purity, and effectiveness.
Conclusion: Understanding IIS in Lifespan Control
The insulin/IGF-1 pathway plays a key role in regulating aging, showcasing a fascinating connection between growth, metabolism, and survival. This system, conserved across species from worms to humans, adapts to environmental conditions, influencing how long organisms live.
Key Insights from IIS Research
Research has consistently shown that tweaking the insulin/IGF-1 pathway can extend lifespan across various species[3]. Lower activity in this pathway has been linked to enhanced stress resistance and longer life. For instance, centenarians often show traits like better glucose tolerance, low fasting insulin levels, and heightened insulin sensitivity[6].
One of the ways reduced IIS activity benefits the body is by activating FoxO transcription factors. This shift promotes lipid oxidation over glucose metabolism, boosts stress resistance, and supports mitochondrial biogenesis[1]. These changes highlight the pathway's connection to stress resistance and healthy aging[3]. Genetic studies have also uncovered links between variations in IIS-related genes, like FOXO3A, and longer lifespans in humans[1].
These discoveries form the foundation for nutritional strategies that MASI Longevity Science incorporates into its supplement formulations.
How MASI Supplements Align with IIS Research
MASI Longevity Science builds on this wealth of evidence, designing supplements that support the cellular benefits of reduced IIS activity. Their NMN formula aids NAD⁺ production, crucial for mitochondrial function and SIRT1 activation. Spermidine promotes autophagy, the process that clears out damaged cellular components to maintain healthy function.
Additionally, Resveratrol and Fisetin work in tandem to activate SIRT1 and reduce inflammation, fostering metabolic adaptability and cellular resilience - key traits of longer life. MASI’s products are crafted to meet high-quality standards and are trusted by more than 352,000 members of the global longevity community. They offer a practical way to apply decades of IIS research to support human health and promote longevity.
FAQs
How does the insulin/IGF-1 pathway impact cellular repair and stress resistance in humans?
The insulin/IGF-1 pathway is essential for aiding cellular repair and helping cells withstand stress. It governs proteins like AKT, which are crucial for boosting cell survival, encouraging growth, and managing glucose metabolism. These functions make cells better equipped to handle damage. Additionally, this pathway plays a role in how cells cope with oxidative stress - a key contributor to the aging process. Interestingly, lower IGF-1 levels have been associated with diminished repair abilities and increased susceptibility to the challenges of aging.
Altogether, this pathway underscores its importance in preserving cellular health and supporting longevity.
How can the insulin/IGF-1 pathway influence aging and what does it mean for my diet and lifestyle?
The insulin/IGF-1 signaling (IIS) pathway plays a crucial role in how our bodies age and how long we live. Studies suggest that dialing down IIS activity - whether through dietary restriction or certain lifestyle adjustments - can boost cellular repair, enhance stress resistance, and improve overall metabolic health. These factors are all linked to healthier aging.
Simple daily habits, like managing your calorie intake or tweaking your macronutrient ratios, might help regulate IIS activity. Doing so could not only extend longevity but also lower the chances of developing age-related diseases, such as cancer. By prioritizing metabolic health and practicing mindful eating, you can make meaningful strides toward long-term wellness.
How does the FOXO3A gene affect longevity, and can its activity be influenced by lifestyle or medical approaches?
The FOXO3A gene plays a significant role in promoting a longer lifespan by managing essential cellular functions, such as reducing oxidative stress and aiding in cell repair. Specific variations in this gene have been linked to healthier aging and extended longevity.
Interestingly, lifestyle choices can impact how FOXO3A functions. Activities like caloric restriction and intermittent fasting are believed to activate this gene. Certain foods, particularly those containing compounds like green tea polyphenols or quercetin, may also support its activity. Additionally, physical stressors like heat exposure and promising medical advancements are being explored for their potential to boost FOXO3A activity, contributing to improved aging processes.
