Sympathetic-parasympathetic system deregulation theory of aging

Abstract

The central nervous system, comprised of the brain, spinal cord, and nerves, includes the autonomic nervous system (ANS) that regulates involuntary functions. Within the ANS, the sympathetic and the parasympathetic nervous systems (SNS and PNS, respectively) control the same bodily functions, but in opposing directions. For example, the sympathetic nervous system elicits our “fight or flight” response, while the parasympathetic system supports “rest and repair” mechanisms in the broadest possible sense. With age, changes occur in how information is transmitted, in energetic requirements and expenditures, and in the ability to respond to change. These alterations with age result in the “hallmarks of aging”, specifically including genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and chronic inflammation. Understanding these age-dependent changes is essential for promoting healthy aging and longevity. We propose that, at the core of aging, there is an imbalance between the SNS and PNS, which provides opportunities for therapeutic intervention.

Introduction: the sympathetic-parasympathetic system (SPS) as the master regulator of aging

Early theories proposing mechanisms for the aging process include those of Max Rubner (1908) and Raymond Pearl’s Rate of Living theory (1928)¹, which stipulate that the faster an organism’s metabolism, the shorter the lifespan, suggesting an inverse relationship between metabolic rate and lifespan. Raymond Pearl’s Rate of Living theory mechanistically supports Max Rubner’s earlier idea that the total metabolic energy used per gram of body weight over a lifetime is similar across different species, implying that an organism’s lifespan is determined by the rate of energy expenditure. Others followed, focusing on free radicals², mitochondria, somatic mutations³, telomere attrition⁴, and inflammation⁵. Here, we provide the rationale for our contention that dysregulation of the SPS: PNS balance is the unifying process that accounts for these changes, that reconciles previous theories, and that could be used to identify new therapeutic targets to enhance and prolong lives.

The ANS, crucial for maintaining homeostasis, comprises efferent pathways (from the SNS and PNS), afferent nerve pathways (visceral afferent fibers), and the central autonomic network, including the insular cortex, amygdala, hypothalamus, periaqueductal gray, and brainstem regions, which encompass the parabrachial nucleus, nucleus of the solitary tract and medulla^6,7. The sympathetic arm of the ANS, the SNS, coordinates responses to stresses (physical, emotional, cognitive) that disrupt functional stability or homeostasis⁸. These responses oppose the loss of homeostasis. Activation of the parasympathetic arm, the PNS, can restore homeostasis⁸. Chronic SNS activation, without PNS recovery, drives excessive divergence from stability or balance. Several studies have highlighted an increasing imbalance that occurs with aging^9–11. This includes hyperreactive SNS, which promotes pro-inflammatory conditions, and enhances inflammaging, an age-related low-grade, sterile, systemic, chronic, and subclinical inflammatory state¹². Inflammaging has become increasingly recognized as an important risk for the onset and progression of several age-related diseases among humans. Overreactive SNS during aging contributes to impairment in endogenous inflammaging strategies caused by diminished blood flow, altered hormone signaling, nerve damage or depletion, leading to reduced responsiveness to stress and increased vulnerability to age-related diseases. However, restoration of overall physiological tone and homeostasis via activation of the PNS could play an anti-inflammatory role mediated through the cholinergic-antiinflammatory pathways (CAPs). At the molecular and cellular levels, these signals are communicated through the vagus nerve and the splenic nerves via the release of acetylcholine to reduce inflammatory sensomes and inflammaging. Accordingly, reduced vagal function can also cause immunosenescence in both innate and adaptive immunity, notably increasing the loads of reactive or senescent macrophages and inflammaging, thereby promoting the development of age-related disease conditions^10,13. Thus, the homeostatic mechanism maintained by the balance between SNS and PNS is crucial for preserving health throughout the lifespan, particularly during aging. From our perspective, we propose that via an imbalance between SNS and PNS, the symptoms of aging are consequences of this balance divergence (genetic, metabolic, immune, growth signaling, etc.)¹³, and balance restoration slows and/or reduces these symptoms. Examples of how SNS:PNS imbalance may affect age-related characteristics are discussed below.

Energy: mitochondrial dysfunction

Chronic SNS activation can cause mitochondrial dysfunction through various pathways. For example, increased catecholamine metabolism and nicotinamide adenine dinucleotide phosphate oxidase promote free radical generation, damaging nuclear and mitochondrial DNA (mtDNA)¹⁴. This can lead to mtDNA release, which, in turn, can activate Toll-like receptor 9 (TLR9)¹⁵ and the stimulator of interferon genes (STING) inflammatory pathways¹⁶. Consequently, inflammatory signaling disrupts the synthesis of antioxidants that protect the cell from damage induced by free radicals¹⁷. Additionally, nuclear DNA damage stimulates chronic p53 activation, leading to interaction with mitochondrial proteins and increased outer membrane permeability¹⁵. Catecholamines increase Ca²⁺ levels in mitochondria, also promoting outer membrane permeability¹⁴. The loss of membrane integrity deregulates apoptotic activity, potentially leading to necrosis (e.g., in atherosclerosis, neurodegeneration), insufficient apoptosis (e.g., in cancer), or desensitized signaling (e.g., senescence, chronic inflammation)¹⁸ (Fig. 1).

Fig. 1. provides a conceptual framework describing the Sympathetic-Parasympathetic (SPS) Deregulation Theory.

SNS activity drives oxidative stress, inflammation, and deregulated nutrient sensing, which in turn induces symptoms of aging. PNS activity reduces these symptoms, slowing the progression of aging. SPS sympathetic-parasympathetic systems, PNS peripheral nervous system, SNS sympathetic nervous system.

PNS activation can support mitochondrial recovery and function by activating mitochondrial α7 nicotinic acetylcholine receptors (α7-nAChR) that reduce excessive Ca²⁺ permeability and mtDNA release¹⁹. In addition, the PNS reduces inflammatory TLR9 and STING activation-dependent cytokine signaling, thereby aiding in antioxidant and anti-inflammatory activity²⁰. Moreover, the PNS enhances the activity of peroxisome proliferator-activated receptor gamma (Ppar-γ) coactivator 1 alpha (PGC-1α). This protein, activated by various signals, including fasting and exercise, acts as a transcriptional coactivator, regulating genes involved in energy metabolism, and promoting metabolic health, notably through mitochondrial biogenesis, fusion, fission, and mitophagy²⁰. PNS activation can reduce endoplasmic reticulum stress, restoring normal cellular responses to damage and inflammation by inhibiting mitochondrial dysfunction¹⁹.

Extracellular homeostasis: inflammation

While excessive SNS stimulation can be destructive, in balance, several aspects of SNS activity can suppress inflammation²¹. For example, catecholamines bind to β-adrenergic receptors, activating adenylate cyclase, which increases cyclic AMP (cAMP) and activates protein kinase A (PKA). PKA can then inhibit nuclear factor kappa B (NF-κB), reducing pro-inflammatory cytokines (e.g., tumor necrosis factor-alpha; TNFα), interleukin (IL)-1β, and IL-6) and enhancing the anti-inflammatory cytokine IL-10²².

Chronic catecholamine release and oxidative stress can also result in pro-inflammatory effects through receptor desensitization and dysregulation, promoting low-grade chronic inflammation (inflammaging)²³. Specifically, although NF-κB is suppressed initially, persistent oxidative stress and excessive catecholamines result in reactive oxygen species (ROS)-mediated damage, enhancing NF-κB-driven inflammasome activity and disrupting cellular homeostasis²³. Additionally, the incidence of cardiovascular diseases increases with aging due to the worsening of chronic catecholamine-induced impairment in contractile reserves caused by aging²⁴. The resulting chronic inflammation feeds back to cause mitochondrial dysfunction, disrupted nutrient sensing (e.g., insulin resistance), and loss of control over healthy protein expression¹⁴.

In contrast, in addition to reducing oxidative stress, PNS balancing through improved vagus nerve function can normalize inflammation through CAPs¹⁷. These parallel pathways utilize acetylcholine (ACh), which binds to α7nAChRs on immune cells²⁵. ACh release may arise directly from vagal efferents (e.g., in the gut), activated choline acetyltransferase-expressing T cells (e.g., in the spleen), or from projections from the nucleus basalis of Meynert in the basal forebrain^17,25. These events trigger a cascade that leads to inhibition of the NF-κB and activation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathways, thereby reducing the transcription of pro-inflammatory cytokines^17,26 (Fig. 1) but increasing the release of specialized pro-resolving mediators (SPMs) from cells of the immune system. The SPMs include protectins, resolvins, lipoxins and maresins. They induce potent anti-inflammatory and pro-resolving mechanisms, enhancing innate immunity by limiting infiltration of polymorphonuclear leukocytes, reducing tissue damage and improving macrophage phagocytosis²⁷. Moreover, agonists of α7nAChRs, such as nicotine, and small heat shock proteins have been shown to mitigate the release of inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-18, thereby delaying aging^28,29.

Intracellular homeostasis: deregulated nutrient sensing and disabled macroautophagy

Cells exist in a balance between anabolic and catabolic activity. Cells can respond to external growth signals through insulin-like growth factor-1 (IGF-1), which activates phosphoinositide 3-kinase (PI3K), and internally through the activation of mechanistic target of rapamycin complex 1 (mTOR), which responds to nutrient availability³⁰. In the absence of sufficient nutrients, the opposing 5’-adenosine monophosphate-activated protein kinase (AMPK) pathway activates autophagy, a process by which cells recycle their intracellular organelles as a source of energy³¹. Autophagy begins with the formation of an autophagosome, which collects damaged organelles, misfolded proteins, and dysfunctional genetic material. The autophagosome fuses with lysosomes to regenerate basic building blocks when nutrients are limited³¹.

Chronic activation of the SNS results in DNA damage repair (DDR) by increasing cAMP levels and activating PKA, which in turn inhibits AMPK, thereby blocking autophagy³². Prolonged SNS activation leads to an inhibition of the degradation and recycling functions within autophagosomes. The result is an accumulation of damaged proteins and organelles in lingering autophagosomes and the cytoplasm³².

In contrast, PNS activity can restore homeostasis³³. For example, PNS activation can normalize insulin signaling that is disrupted by suppressors of cytokine signaling expressed upon inflammation and normalizes PI3K and mTOR activity. Additionally, PNS effects on the AMPK pathway are principally protective, i.e., supportive of a healthy dynamic equilibrium³³.

Information: epigenetic alterations

Epigenetic mechanisms, including DNA methylation, histone modification, and non-coding RNAs, regulate cellular differentiation. The loss of epigenetic control deregulates protein expression, leading to apoptosis, senescence, and age-related diseases¹⁸. Oxidative stress triggered by chronic SNS activation increases ROS production, which impairs the function of DNA methyltransferases that maintain epigenetic methylation². Inflammatory cytokines associated with chronic SNS activation, such as TNFα, IL-1β and IL-6, can disrupt histone acetyltransferases and deacetylases. These disruptions affect chromatin structure and gene transcription³⁴. Conversely, activation of the PNS appears to reduce oxidative stress, normalize inflammation, and stabilize epigenetic controls³⁵ (Fig. 1).

Remaining hallmarks

Chronic SNS activity accelerates telomere attrition and genetic instability because DNA is susceptible to ROS-mediated oxidative stress, and inflammatory cytokines impair telomerase¹⁵ and DDR mechanisms³². Similarly, oxidative stress impairs stem cell renewal¹⁵, leading to stem cell exhaustion and telomere attrition, which in turn result in mitochondrial dysfunction and cellular senescence-a state of cell cycle arrest that significantly contributes to aging by promoting inflammation, tissue dysfunction, and age-related diseases¹⁸. Conversely, PNS activity slows ROS production and reduces inflammation, promoting telomerase activity and DDR mechanisms^33,35, and enhancing mitochondrial capacity to activate and complete apoptosis, clearing senescent cells^19,20,31. The PNS, through the vagus nerve, regulates inflammation, potentially modulating cellular senescence by influencing the senescence-associated secretory phenotype, such as inflammatory cytokines, growth factors and proteases^10,36.

Epigenetic drift and disabled autophagy, exacerbated by chronic SNS activity, have bidirectional relationships with the loss of proteostasis¹⁶. This aspect of homeostasis is restored by α7nAChR activation¹⁷. Similarly, chronic SNS-triggered inflammation and ROS production lead to impaired cell-cell and cell-extracellular matrix interactions (altered extracellular communication)³⁷, which are reversible by PNS activation^17,25.

Imbalances among microbiomes of the gut, skin, airways, etc., impair nutrient absorption, oxygenation, immune tolerance, and other critical aspects of homeostasis^23,32. This dysbiosis is promoted by cortisol and cytokine release triggered by chronic SNS activation (e.g., altered gut motility, mucus production, and increased gut permeability), by pathogenic bacterial overgrowth, and by systemic immune dysfunction^32,38. The reduction in PNS activity associated with aging results in greater inflammation, heightened cortisol levels, and a disrupted gut microbiome^10,38.

Future opportunities

PNS balancing has long been recognized as a potential pathway to recovery, and various cultures have adopted healing and social practices that increase PNS activity³⁹. Recently, technologies for directly reactivating the PNS (e.g., vagus nerve stimulation, or VNS) have been developed for the treatment of multiple conditions, such as refractory epilepsy, treatment-resistant depression, migraine, and schizophrenia^40–42. Hand-held, non-invasive wellness devices are being deployed in the U.S. military to enhance cognitive and performance. Some devices place electrodes on the ear to stimulate the auricular branch of the vagus nerve (auricular) transcutaneously, known as auricular VNS^43,44. Others use electrodes placed on the skin of the neck to stimulate the vagus nerve (cervical), termed non-invasive VNS^41,45. Regulation of immune activity and mitochondrial dysfunction are demonstrable benefits of VNS, strongly suggesting protective and anti-aging effects^35,40,41. Collectively, the data support a unifying hypothesis in which the balance between SPS and PNS, through multiple molecular and cellular mechanisms, integrates the hallmarks of aging and may serve as an important therapeutic target. Thus, studies examining the longevity-enhancing potential of VNS are warranted.

Author contributions

Joseph P. Errico: Conceptualization, Visualization, Writing—original draft, Writing—review and editing. Benneth Ben-Azu: Writing—Visualization, formatting, review and editing. Makenna Gargus: Writing—revision. M. Karen Newell Rogers: Conceptualization, Visualization, Writing—review and editing. Marie-Ève Tremblay: Conceptualization, Visualization, Writing—review and editing. M. Karen Newell Rogers and Marie-Ève Tremblay: Are Co-senior authors. The manuscript was revised and approved by all authors.

Data availability

No datasets were generated or analyzed during the current study.

Competing interests

The authors declare no competing interests.