By: Linda P. Fried
In: Cold Spring Harbor Perspectives in Medicine, 2016 Jun 1.
Date: 2016
Summary
- Life span has expanded.
- Added about 30 years in life span over the last 100 years.
- Mostly due to:
- Public health interventions targeting infectious diseases.
- Decreased early childhood and maternal mortality.
- Challenge: how to maximize health and vitality across expanded lifespan.
- Compression of morbidity to the latest point in the human life.
- Prevention of chronic diseases.
- At every age and stage of life.
- If you arrive at 70 at good health, reasonable chance of remaining healthy.
- Prevention and treatment of frailty.
- Prevention of chronic diseases.
- Model intervention: physical activity.
- Compression of morbidity to the latest point in the human life.
Key Takeaways
- Homeostasis and resilience = healthy physiological and biological systems.
- Ability to adapt, respond to injury and stress.
- These systems are complex.
- Systems mutually affect or regulate each other.
- Frailty = dysregulated systems.
- Loss of adaptive capacity.
- Especially apparent in response to stressors, challenges.
- Distinct phenotype.
- Mostly associated with dysregulation of energy (low strength, low energy, weight loss).
- Independent predictor of mortality.
- Fix: physical activity.
- Improves energy production and use.
- Complex, low-risk intervention.
- Preserves or improves many functions compromised in frailty.
Key Concepts
Age and disease
- Disease and chronological age not necessarily tied together.
- Disease (of specific organ systems) can be a process distinct from aging.
- Atherosclerotic disease of the heart, brain, and peripheral vasculature.
- Disease (of specific organ systems) can be a process distinct from aging.
- Disease is not inevitable with advance in age.
- Many chronic diseases are preventable.
- Subject to risk factors: physical activity, smoking, diet, inflammation.
- Both disease and age are factors in mortality.
- Chronic disease are reliable predictors of mortality.
- Age becomes a factor above 85 years of age.
- Concept of biological and chronological age.
- Altered physiological regulation and function across multiple systems.
Frailty
- After about age 70, a new phenotype emerges: frailty.
- Independent predictor of mortality.
- Medical syndrome.
- A constellation of symptoms and signs.
- When present in critical mass predicts outcomes and identifies a distinct underlying pathophysiology.
- Predicts outcomes more than any other one or two factors.
- Symptoms:
- Muscle weakness (grip strength).
- Slowed gait (time to walk about 15 feet).
- Low physical activity (<270 kcal/week).
- Sense of low energy or exhaustion (“everything is an effort”).
- Unintentional weight loss (>10 pounds).
- Chronic, progressive.
- Twice as prevalent in women as men.
- By age 85, 25% of population manifests 3-5 components of frailty.
- Progression:
- Begins with declines in strength, walking speed, physical activity.
- Progresses to low energy or exhaustion and unintended weight loss.
- Frailty is the consequence of a trade-off between robustness and fragility.
- Robustness contributing to homeostasis and maintenance of functionality.
Underlying mechanisms of frailty
- Frailty emerges from the dysregulation of complex adaptive systems.
- Systems that maintain organismal homeostasis and resilience.
- Resilience: response to stress and injury.
- Systems decline with age.
- Systems that maintain organismal homeostasis and resilience.
- Physiological systems that decline:
- Hormonal deficiency (estrogen, testosterone, IGF-1).
- Impaired insulin sensitivity.
- Increased inflammation (cytokine excess).
- Biological systems that decline:
- Mitochondrial dysfunction (lower ATP).
- No dominating patterns.
- Only predictor is the number of systems dysregulated.
- Not any particular system.
- Complex.
- Change in systems affect multiple components of the frailty phenotype.
- Systems mutually affect or regulate each other (feed-forward feed-back loops).
- Dysregulation > threshold number = critical loss of homeostatic adaptive capacity = frailty.
- Frailty is an emergent state.
- Loss of resilience becomes apparent in response to stressors, challenges.
- Frailty = marker of a severe end stage of biologic aging.
- Underlying dysregulation of the complex dynamical systems that maintain a resilient organism.
- Dysregulation of the system becomes evident in the presence of stressors.
- Leading to adverse health outcomes occur when the system is challenged.
Interventions
- Interventions targeting only one of the dysregulated systems have not been able to prevent frailty.
- Evidence that frailty is a complex system problem.
- Energy dysregulation: the critical entry point to development of frailty.
- Altered energy intake (diet).
- Unintentional weight loss.
- Physical exhaustion.
- Muscle weakness.
- Altered glucose metabolism.
- Lower muscle efficiency.
- Decline in mitochondrial function.
- Intervention should focus on improving energy production and use.
- Shift the entire complex system of function.
- Physical activity: complex intervention.
- Physical activity itself is correlated with lower mortality.
- Reverse: decline in physical activity both predicts and worsens frailty.
- Physical activity preserves or improves many different functions compromised in frailty.
- Physical activity maintains mitochondrial function, lowers ROS.
- General organization of metabolic apparatus is far better preserved in individuals who exercised regularly.
- Delay onset and progression of frailty.
- Low-risk.
- Simultaneously up-regulates many systems that mutually regulate each other in combination.
- The whole organism could be re-tuned to a higher functional level.
- Physical activity itself is correlated with lower mortality.