Longevity pathways

Longevity pathways are a collection of molecular pathways that have been shown to influence lifespan and healthspan in various organisms, ranging from yeast to mammals. Understanding these pathways is crucial for researchers aiming to develop interventions that can extend healthy human lifespan.

Longevity pathways represent molecular and genetic networks that modulate lifespan and healthspan. These pathways have been identified primarily through the study of model organisms where genetic or pharmacological manipulations resulted in lifespan extensions. The distinction between longevity pathways and other essential body processes is often blurry, as the very processes that support life also modulate its duration and quality. However, the primary distinction is that longevity pathways have demonstrated a direct influence on extending or shortening lifespan when modulated.

Longevity pathways classification

Most of these longevity pathways indicate an organism to preserve energy, and resources and to await for a more bountiful time in order to acquire resources. It is about the optimization of resources and redistribution of resources with survival in mind.

  1. Molecular Activity:
    • Signal Transduction: Many longevity pathways involve a series of molecular signals where an external signal is relayed through cellular components to result in a change in cellular activity. For instance, nutrient signals can modulate the activity of the mTOR pathway, which in turn influences cellular growth, autophagy, and more.
    • Protein Activity Modulation: Protein function can be altered through post-translational modifications like phosphorylation or acetylation. For instance, sirtuins deacetylate target proteins, altering their function and influencing processes like DNA repair and metabolism.
    • Metabolic Regulation: The AMPK pathway responds to cellular energy levels and acts to restore energy balance by promoting catabolic processes that generate ATP and inhibiting anabolic ones.
  2. Genetic Activity:
    • Gene Expression: Longevity pathways often influence which genes are turned on or off in response to various signals. For instance, the insulin/IGF-1 signaling pathway influences the expression of genes that control development, metabolism, and other processes in response to insulin and nutrient signals.
    • Epigenetic Modifications: These are changes in gene activity not caused by alterations in the DNA sequence. Factors like DNA methylation or histone modifications can change over time, influencing aging. Sirtuins, for example, play roles in epigenetic modifications.
    • DNA Repair and Integrity: Maintaining the integrity of the genetic code is crucial for longevity. Some longevity pathways, like those involving certain sirtuins, play roles in DNA repair processes.
  3. Distinguishing Longevity Pathways Genetically:
    • Evolutionary Conservation: Longevity pathways tend to be conserved across multiple species. The insulin/IGF-1 pathway, for instance, affects lifespan in yeast, worms, flies, and mammals. Such conservation suggests these pathways play fundamental roles in determining lifespan.
    • Direct Lifespan Influence: While many genetic and molecular pathways are essential for life, not all directly modulate lifespan when altered. Longevity pathways are distinguished by clear evidence that their modulation (via genetic mutations, overexpression, or pharmacological intervention) extends or decreases lifespan in model organisms.
    • Interplay with Environmental Inputs: Longevity pathways typically interface with environmental cues like nutrient availability, stress, or toxins. The mTOR pathway, for instance, is responsive to nutrient signals, and its modulation can influence lifespan depending on dietary conditions.

In summary, longevity pathways encompass molecular and genetic networks that directly modulate lifespan and healthspan. While they are interconnected with essential body processes, their direct influence on aging, conserved roles across species, and often their interface with environmental cues distinguish them in the context of longevity research.

Longevity pathways list

Here’s a breakdown of known major longevity pathways, how they can be grouped, and a brief description of each. Unfortunately, the exact mechanisms of how they work are often not known entirely and there may be more longevity pathways we are unaware of.

  • Insulin/IGF-1 Signaling (IIS) Pathway
    • Organisms ranging from worms (C. elegans) to mice have demonstrated increased lifespan when components of this pathway are knocked down or mutated.
    • In C. elegans, mutations in the daf-2 gene, which encodes an insulin/IGF-1 receptor, can double the worm’s lifespan(1).
  • mTOR Pathway
    • mTOR (mechanistic Target of Rapamycin) is a protein kinase that regulates cell growth, proliferation, and survival.
    • Inhibition of the mTOR pathway, such as with rapamycin, has been shown to extend lifespan in yeast, worms, flies, and mice(2).
  • AMPK Pathway
    • AMPK (AMP-activated protein kinase) is a cellular energy sensor. When activated, it promotes catabolic pathways that produce ATP and inhibits anabolic pathways.
    • Activators of AMPK, like metformin, have been proposed to have lifespan-extending effects(3).
  • Sirtuin Pathway
    • Sirtuins are a family of NAD+-dependent protein deacetylases.
    • Overexpression of certain sirtuins can extend lifespan in various organisms, such as yeast (Sir2), worms, and flies(4).
  • Mitochondrial Function
    • Mitochondria, the cell’s energy producers, are crucial for longevity.
    • Interventions that improve mitochondrial function or biogenesis, such as exercise and caloric restriction, can influence lifespan(5).
  • Nrf2 Pathway
    • Nrf2 (nuclear factor erythroid 2-related factor 2) is a major regulator of antioxidant defense in the cell.
    • Activation of the Nrf2 pathway can protect against oxidative stress and has implications for longevity(6).
  • DNA Damage Response and Repair
    • Maintaining DNA integrity is critical for cellular function and longevity.
    • Mutations affecting DNA repair mechanisms can significantly reduce lifespan, while enhancing these mechanisms may extend lifespan(7).

It’s important to note that while these pathways have been shown to influence longevity in laboratory settings and in various organisms, translating these findings to humans in a way that leads to meaningful lifespan extension is a complex challenge.

References

  1. Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. Nature, 366(6454), 461-464.
  2. Harrison, D.E., et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 460(7253), 392-395.
  3. Martin-Montalvo, A., et al. (2013). Metformin improves healthspan and lifespan in mice. Nature Communications, 4, 2192.
  4. Tissenbaum, H.A., & Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410(6825), 227-230.
  5. López-Lluch, G., et al. (2006). Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proceedings of the National Academy of Sciences, 103(6), 1768-1773.
  6. Sykiotis, G.P., & Bohmann, D. (2008). Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Developmental Cell, 14(1), 76-85.
  7. Rossi, D.J., Bryder, D., Seita, J., Nussenzweig, A., Hoeijmakers, J., & Weissman, I.L. (2007). Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature, 447(7145), 725-729.

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