How the HPA Axis Changes With Age

The hypothalamic-pituitary-adrenal (HPA) axis is the neuroendocrine system that governs the body's glucocorticoid response to stress. Its terminal effector in humans is cortisol, a steroid hormone of the glucocorticoid class (molecular formula C21H30O5; molecular weight 362.46 g/mol). The axis is a three-tier cascade: hypothalamic corticotropin-releasing hormone (CRH) drives pituitary adrenocorticotropic hormone (ACTH) release, which in turn drives adrenal cortisol synthesis. Age-related change in this axis is not a single event but a shift in the amplitude, timing and negative-feedback sensitivity of the cascade, and it is studied across human cohorts, animal models and in vitro preparations.

The work centres on the CRH/ACTH/cortisol signalling cascade and its feedback regulation through the glucocorticoid receptor family, with upstream modulation by noradrenergic input from the locus coeruleus.

Research Studies

HPA axis activation and sleep restriction in older men and postmenopausal women

A dedicated study examined how HPA axis activation occurs under sleep restriction in older men and postmenopausal women, and in parallel evaluated deactivation of the hypothalamic-pituitary-gonadal (HPG) axis under the same condition [6]. The protocol also assessed cognitive function associated with sleep restriction, including food intake and food cravings [6]. This is the most directly age-relevant human design in the evidence set, because the enrolled population is defined by reproductive ageing.

HPA axis activation and sleep restriction in a general adult cohort

A companion study applied the same two-axis question — HPA activation and HPG deactivation under sleep restriction — to a broader adult population, again with cognitive, food intake and food craving measures [7]. Comparing the two designs is useful because the axis response to a controlled stressor can be read against the age-defined cohort in [6].

Noradrenergic drive of CRH release in post-traumatic stress disorder

In post-traumatic stress disorder (PTSD), the described mechanism is a complex noradrenergic dysregulation: the amygdala activates the hypothalamus to release excessive corticotropin-releasing factor (CRF), which activates the HPA axis and leads to high nocturnal cortisol levels with EEG changes and increased arousals [1]. In the same account, the locus coeruleus releases excess norepinephrine, which interferes with the transition to non-REM sleep and suppresses the stability of REM sleep [1]. This study is relevant to ageing because it links a specific upstream driver — noradrenergic tone — to the nocturnal cortisol pattern that is itself a target of age research.

HPA axis dysregulation in chronic prostatitis/chronic pelvic pain syndrome

A review of neuroendocrine mechanisms in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) synthesised five years of literature on neuropeptide function, HPA axis dysregulation, sympathetic nervous system signalling and glial cell activity [3]. The review frames the limited efficacy of conventional therapies as a reason to look at deeper regulatory mechanisms rather than infection and local inflammation alone [3].

HPA axis signalling in cancer-related psychiatric disorders

In oncological psychiatry, the pathophysiology of cancer-related psychiatric disorders is described as multifactorial and tied to several neuropsychological and neurobiological factors, including cytokine production [2]. The same source notes that psychiatric disorders in cancer patients are frequently underdiagnosed, and that they are not merely secondary complications but may actively contribute to poor oncological outcomes [2].

Polyphenol intake and HPA axis regulation

A study of muscadine wine polyphenols hypothesised that both acute and chronic intake would improve cognitive performance and mood through regulating the HPA axis, alleviating inflammation and oxidative stress, and/or inhibiting monoamine oxidase activities [5]. The hypothesis is stated as a mechanism to be tested, not as an established effect.

Cortisol and BDNF response to isometric neck exercise in cervicogenic headache

Cervicogenic headache is described as a secondary headache arising from referred pain from the cervical spine, associated with decreased cervical range of motion, decreased sleep quality, increased stress, disturbed mood and altered physiologic chemicals, and it is reported as more prevalent in females [4]. The study measures cortisol and BDNF levels in smartphone users undergoing isometric neck exercises [4].

Exercise intensity and ACTH/cortisol response in Thoroughbred racehorses

In horses, exercise is treated as a physiological challenge that induces intensity-dependent HPA axis responses, and the hypothesis tested was that training and racing sessions induce different degrees of HPA axis activation [10]. This is an animal model; the finding concerns equine adrenal response and should not be read across to human physiology without further work.

α7 nicotinic receptor signalling and CRH neurons in the paraventricular nucleus

Dysregulation of the HPA axis is described as a central feature of stress-related affective disorders, with CRH neurons in the hypothalamic paraventricular nucleus initiating neuroendocrine stress responses [11]. The work reports that activation of the α7 nicotinic acetylcholine receptor promotes anxiety- and depressive-like behaviours associated with CREB/CRH signalling in that nucleus [11]. This is a mechanistic, non-human line of evidence.

Adaptogens and stress resistance

A narrative review describes adaptogens as primarily plant-derived bioactive compounds that enhance resistance to physical, chemical and biological stressors, with proposed relevance to stress-related disorders, neurodegenerative disease, inflammation and ageing [8]. The review is a synthesis of existing understanding and future perspectives rather than a primary experimental result.

Schisandrin B and anxiety-like behaviour in rats

In rats displaying anxiety-like behaviour, Schisandrin B was examined for anxiolytic effects using the elevated plus-maze and open field tests, with reported effects at a dose of 10 mg/kg alongside enhancement of hippocampal synaptic plasticity and restoration of the intestinal barrier [9]. This is an animal study; the dose is a laboratory administration in rats and carries no human implication.

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Sources

• [1] Identification of Physiological Sleep Indices That Reflect Clinical Improvement and Reduction in Stress Biomarkers After Stellate Ganglion Block in Patients With Posttraumatic Stress Disorder (PTSD) — https://clinicaltrials.gov/study/NCT07618611
• [2] MEOP - Multidimensional Evaluations in Oncological Psychiatry — https://clinicaltrials.gov/study/NCT07406113
• [3] Current research hotspots and difficulties of chronic prostatitis/chronic pelvic pain syndrome: neuroendocrine mechanism — https://europepmc.org/article/PMC/PMC12821347
• [4] Effect of Isometric Neck Exercises on Cervicogenic Headache Symptoms, Cortisol and BDNF Levels Among Smart Phone Users — https://clinicaltrials.gov/study/NCT07354776
• [5] Use Muscadine Wine Nutraceuticals to Improve Brain Health, Cognition, and Mental Health — https://clinicaltrials.gov/study/NCT05541887
• [6] Hormonal Mechanisms of Sleep Restriction - Axis Study in Older Men and Postmenopausal Women — https://clinicaltrials.gov/study/NCT04037605
• [7] Hormonal Mechanisms of Sleep Restriction - Axis Study — https://clinicaltrials.gov/study/NCT03142893
• [8] Phyto adaptogens in stress management and health optimization: Current understanding and future perspectives — https://pubmed.ncbi.nlm.nih.gov/42721096/
• [9] Mechanistic Study of Schisandrin B in Alleviating Anxiety-Like Behaviors in Rats via Enhancement of Hippocampal Synaptic Plasticity and Restoration of the Intestinal Barrier — https://pubmed.ncbi.nlm.nih.gov/42718869/
• [10] Training- and competition-related changes on circulating adrenocorticotropic hormone and cortisol response in Thoroughbred Racehorses — https://pubmed.ncbi.nlm.nih.gov/42697342/
• [11] α7 nicotinic acetylcholine receptor activation promotes anxiety- and depressive-like behaviors associated with CREB/CRH signaling in the hypothalamic paraventricular nucleus — https://pubmed.ncbi.nlm.nih.gov/42685894/