The age-related rise in circulating norepinephrine
Multiple lines of evidence confirm that plasma norepinephrine concentrations rise with age, even at rest. This phenomenon is a hallmark of the age-related changes in the sympathetic nervous system (SNS), which controls the 'fight or flight' response. The SNS becomes overactive with age, contributing to a state of chronic sympathetic overactivity.
Why norepinephrine levels climb
- Reduced clearance: A primary driver of higher norepinephrine (NE) levels is a decrease in the body's ability to clear it from the bloodstream. The neuronal reuptake transporter, which recycles NE back into nerve terminals, becomes less efficient with age. In older individuals, the extraction of norepinephrine from the bloodstream is less effective, particularly in the heart.
- Enhanced spillover: While the actual firing rate of sympathetic nerves in skeletal muscle may not increase with age, the amount of NE that 'spills over' into the circulation increases. This is particularly notable in the heart, where impaired reuptake leads to higher levels of NE in the synaptic cleft and, consequently, higher circulating plasma levels.
- Central nervous system changes: Cerebrospinal fluid (CSF) norepinephrine levels also show an age-related increase in some studies, suggesting that changes are not limited to the peripheral nervous system. Research indicates that this higher central NE activity is linked to a decline in certain cognitive functions, like attention and executive performance.
The paradox: High levels, blunted response
While circulating norepinephrine increases with age, the body's physiological response to it can become blunted or impaired, especially in the cardiovascular system. This is known as beta-adrenergic receptor desensitization. The heart and blood vessels become less responsive to catecholamines over time, reducing the effectiveness of the body's fight-or-flight response.
The mechanism of reduced responsiveness
As we age, the beta-adrenergic receptor-adenylyl cyclase system in the heart shows significant changes. This pathway is crucial for modulating heart rate and contractility in response to stress. In aging hearts, a reduction in the density and function of these beta-adrenergic receptors, particularly the $\beta_1$ subtype, contributes to a diminished response to adrenergic stimulation.
Comparison of Norepinephrine System in Young vs. Older Adults
| Aspect | Young Adults | Older Adults |
|---|---|---|
| Resting Plasma NE | Lower | Significantly higher |
| NE Neuronal Reuptake | More efficient | Reduced, leading to greater spillover |
| NE Spillover from Heart | Lower at rest and during stress | Higher at rest and greatly increased during stress |
| Beta-Adrenergic Receptor Sensitivity | High, robust physiological response | Reduced sensitivity and density |
| Heart Rate Response to Stress | Strong and dynamic | Often blunted, despite higher NE |
| Cognitive Function and NE | Optimal activity enhances cognition | Excess activity linked to poorer cognitive performance |
Implications for health and disease
The age-related increase in norepinephrine and the corresponding desensitization of adrenergic receptors have major health consequences, particularly for the cardiovascular system. This perpetual state of sympathetic overactivity is linked to an increased risk of hypertension, cardiac arrhythmias, and heart failure.
- Cardiovascular strain: The combination of higher circulating norepinephrine and a less responsive heart can place significant stress on the cardiovascular system. Elevated NE drives vasoconstriction, while the reduced effectiveness of beta-receptors limits the heart's compensatory ability to increase heart rate and pump efficiency.
- Cognitive effects: In the central nervous system, excessive noradrenergic activity has been associated with impaired cognition, including deficits in attention and executive function, as demonstrated in studies of cerebrospinal fluid norepinephrine. An imbalance in the noradrenergic system may also contribute to behavioral disturbances in conditions like Alzheimer's disease.
- Role in stress response: The heightened noradrenergic response to stress that occurs with age means that older adults experience greater increases in plasma norepinephrine during psychological stress compared to younger individuals. However, this heightened response does not necessarily translate to a more effective physiological adjustment due to the underlying receptor desensitization.
Conclusion
In summary, research consistently shows that circulating norepinephrine levels tend to increase with age, driven primarily by a decline in the body's ability to clear the neurotransmitter rather than an increase in its initial release from sympathetic nerves. This elevated baseline of norepinephrine, combined with a paradoxical desensitization of adrenergic receptors, contributes to sympathetic nervous system overactivity. This has significant implications for cardiovascular health, stress response, and cognitive function in older adults. Understanding this complex interplay is crucial for developing targeted interventions to mitigate the adverse effects of aging on the sympathetic nervous system.
