Understanding the Geroscience Framework
For decades, aging was viewed as an inevitable decline. However, a new field called geroscience has reframed this perspective, proposing that aging is a treatable process with distinct biological mechanisms. At a key 2014 summit, the Trans-NIH Geroscience Interest Group (GSIG) identified seven pillars of aging, representing the core cellular and molecular processes that, when disrupted, lead to age-related diseases and functional decline. Instead of being independent factors, these pillars are highly interconnected, creating a complex web of influence on a person's overall healthspan.
The Seven Interconnected Pillars of Aging
The following sections dive into each of the seven pillars, explaining their role in healthy biological function and how their dysregulation contributes to aging.
Pillar 1: Macromolecular Damage
Macromolecules are the large, essential molecules of life, including DNA, proteins, and lipids. Throughout a person's life, these molecules accumulate damage from various sources, such as oxidative stress and radiation. This damage disrupts normal cellular function and can lead to genetic mutations. The body has natural repair mechanisms, but their efficiency diminishes with age.
Sources and Effects of Macromolecular Damage
- Oxidative stress: An imbalance between free radicals and antioxidants leads to damage. This is often caused by natural metabolic processes.
- Glycation: The non-enzymatic attachment of sugar molecules to proteins and lipids, which can impair their function.
- Accumulation of damage: Over time, the buildup of unrepaired damage contributes to cellular dysfunction and tissue aging.
Pillar 2: Epigenetics
Epigenetics refers to the changes in gene expression that do not involve alterations to the underlying DNA sequence. These are essentially chemical modifications that turn genes on or off. As a person ages, these epigenetic patterns, or the 'epigenetic landscape,' can drift, leading to altered gene expression. This can cause cells to lose their proper identity and function, contributing to age-related disease.
Epigenetic Drift and Aging
- DNA methylation: Changes in the methylation patterns on DNA can silence or activate genes incorrectly.
- Histone modification: The proteins around which DNA is wrapped can be chemically modified, affecting gene accessibility.
- Cellular memory loss: Epigenetic drift can cause cells to 'forget' their function, contributing to a decline in tissue health.
Pillar 3: Inflammation (Inflammaging)
Chronic, low-grade, sterile inflammation that increases with age is known as "inflammaging." It is a constant feature of aging that contributes to a wide range of age-related diseases, including cardiovascular disease, dementia, and cancer. Unlike the acute inflammation that is part of the immune response to injury, inflammaging is persistent and systemic.
The Cycle of Inflammaging
- Increased cellular stress: Chronic stress from damaged macromolecules or metabolic dysfunction triggers an inflammatory response.
- Senescent cells: "Zombie cells" that have stopped dividing but refuse to die accumulate and secrete pro-inflammatory signals.
- Immune system changes: The aging immune system becomes less effective at resolving inflammation, perpetuating the cycle.
Pillar 4: Adaptation to Stress
Adaptation to stress, or stress response, is the body's ability to maintain homeostasis in the face of various challenges. Over time, the body's ability to respond effectively to stressors diminishes. The systems that once provided resilience, such as heat shock proteins, become less efficient. This dysregulated stress response makes an aging body more vulnerable to damage.
Mechanisms of Diminished Stress Response
- Heat shock proteins: These proteins help refold damaged proteins, but their production decreases with age.
- Antioxidant defenses: The body's natural antioxidant systems become less potent, allowing oxidative stress to increase.
- Cellular signaling: Communication pathways that trigger stress responses become less responsive.
Pillar 5: Proteostasis
Proteostasis, or protein homeostasis, is the cellular process that controls the quality and quantity of proteins. It involves a delicate balance of protein synthesis, folding, trafficking, and degradation. As people age, this system can become disrupted, leading to the accumulation of misfolded and aggregated proteins, a hallmark of many neurodegenerative diseases.
| Healthy Proteostasis | Disrupted Proteostasis |
|---|---|
| Efficient protein folding: Chaperone proteins guide proper protein shape. | Protein aggregation: Misfolded proteins clump together, forming toxic aggregates. |
| Effective degradation: Unnecessary or damaged proteins are cleared by the proteasome and autophagy. | Impaired waste removal: The cellular machinery for breaking down and recycling proteins becomes less effective. |
| Balanced synthesis: Protein production is matched to cellular needs. | Uncontrolled synthesis: Overproduction of certain proteins can overwhelm cellular systems. |
Pillar 6: Metabolism
Metabolism encompasses the chemical processes that occur within a living organism to maintain life. With age, metabolic function often declines, leading to conditions like insulin resistance and altered nutrient sensing. A key aspect of geroscience is understanding how interventions like caloric restriction can influence longevity by modulating metabolic pathways.
Key Metabolic Pathways in Aging
- Insulin/IGF-1 signaling: Reduced activity in this pathway is linked to increased lifespan.
- mTOR pathway: Regulates cell growth and metabolism; inhibiting it has been shown to extend lifespan in some model organisms.
- AMPK pathway: Senses low energy states and promotes cellular repair and longevity.
Pillar 7: Stem Cells and Regeneration
Stem cells are the body's reserve of undifferentiated cells, capable of developing into specialized cell types and of replenishing damaged tissues. Stem cell exhaustion, or the decline in their number and function, is a significant pillar of aging. This impairs the body's ability to repair and regenerate, leading to weaker tissues and organs.
How Stem Cells Change with Age
- Reduced numbers: The number of functional stem cells in various tissues decreases over time.
- Impaired function: Remaining stem cells become less potent and less efficient at repairing tissue.
- Altered microenvironment: The surrounding tissue no longer provides optimal support for stem cell function.
Connecting the Pillars and Implications for Interventions
Crucially, these seven pillars are not independent. Dysregulation in one pillar can cascade and affect others, creating a feedback loop that accelerates aging. For example, metabolic dysfunction can increase oxidative stress, which causes macromolecular damage and fuels inflammaging. The interconnectedness of these pillars offers hope for intervention. Strategies that target one pillar, such as regular physical exercise, can have positive effects across multiple pillars simultaneously. Regular physical activity, for instance, can enhance stress adaptation, improve metabolic function, and support proteostasis.
This framework of the seven pillars provides a comprehensive biological map of the aging process, moving beyond simple chronological age to focus on the underlying mechanisms that drive disease and decline. By understanding and addressing these interconnected pillars, researchers hope to develop new strategies to extend healthspan—the number of years a person lives in good health—and not just lifespan.
For more detailed information on research into these mechanisms, visit the National Institute on Aging's website National Institute on Aging: The Geroscience Initiative.
