The aging process brings about a complex re‑wiring of the mechanisms that control food intake. While many factors contribute to the well‑known decline in appetite among older adults, two hormones—ghrelin and leptin—play especially pivotal roles. Understanding how these signals change with age helps clarify why appetite regulation becomes less reliable in later life and informs the scientific basis for future interventions aimed at maintaining healthy body weight in older populations.
Ghrelin: The Hunger Hormone
Ghrelin, a 28‑amino‑acid peptide primarily secreted by the oxyntic glands of the stomach, is the only known peripheral orexigenic (appetite‑stimulating) hormone. Its secretion follows a characteristic circadian rhythm, peaking shortly before meals and falling after food intake. Ghrelin exerts its effects through the growth hormone secretagogue receptor (GHS‑R1a) located in the arcuate nucleus of the hypothalamus, where it activates neuropeptide Y (NPY) and agouti‑related peptide (AgRP) neurons, both potent stimulators of feeding behavior.
Beyond its central actions, ghrelin influences peripheral metabolism by:
- Promoting gastric motility and acid secretion, facilitating nutrient digestion.
- Modulating glucose homeostasis through antagonism of insulin secretion.
- Enhancing adipogenesis via activation of peroxisome proliferator‑activated receptor‑γ (PPAR‑γ) in adipocytes.
These multifaceted actions make ghrelin a key integrator of energy status and feeding drive.
Leptin: The Satiety Hormone
Leptin, a 16‑kDa adipokine, is produced proportionally to the amount of stored triglycerides in adipose tissue. It circulates in the bloodstream and crosses the blood‑brain barrier to bind leptin receptors (Ob‑R) in the hypothalamic ventromedial nucleus (VMN) and the arcuate nucleus. Activation of these receptors suppresses NPY/AgRP neurons while stimulating pro‑opiomelanocortin (POMC) neurons, thereby reducing food intake and increasing energy expenditure.
Leptin also participates in:
- Regulation of the sympathetic nervous system, influencing thermogenesis.
- Modulation of immune function, linking nutritional status to inflammation.
- Interaction with the hypothalamic–pituitary–adrenal axis, affecting stress responses.
In younger, metabolically healthy individuals, circulating leptin levels provide a reliable feedback signal that curtails excessive caloric intake.
Age‑Related Alterations in Ghrelin Secretion
Multiple cross‑sectional and longitudinal studies have documented a blunted pre‑prandial ghrelin surge in older adults. Key observations include:
- Reduced fasting ghrelin concentrations: Elderly participants (≥ 70 years) often exhibit 10–20 % lower fasting ghrelin levels compared with middle‑aged controls, even after adjusting for body mass index (BMI) and fat mass.
- Attenuated post‑prandial suppression: The typical decline in ghrelin after a meal is less pronounced, suggesting a dysregulated feedback loop.
- Shift in ghrelin isoforms: The ratio of acylated (active) ghrelin to des‑acyl ghrelin declines with age, potentially diminishing the hormone’s orexigenic potency.
Mechanistically, age‑related gastric mucosal atrophy, reduced vagal afferent sensitivity, and alterations in the expression of ghrelin‑O‑acyltransferase (GOAT)—the enzyme responsible for ghrelin acylation—contribute to these changes. The net effect is a weaker hunger signal that may partially explain the reduced meal initiation observed in many seniors.
Age‑Related Alterations in Leptin Sensitivity
While circulating leptin concentrations tend to rise with advancing age—largely reflecting the increase in adipose tissue mass—older adults often develop leptin resistance, characterized by:
- Impaired transport across the blood‑brain barrier: Age‑associated endothelial dysfunction reduces leptin’s access to hypothalamic receptors.
- Down‑regulation of Ob‑R expression: Post‑mortem analyses reveal decreased leptin receptor density in the VMN of aged rodents.
- Inflammatory signaling interference: Chronic low‑grade inflammation (“inflammaging”) activates suppressor of cytokine signaling‑3 (SOCS‑3), which antagonizes leptin receptor signaling pathways.
Consequently, despite higher peripheral leptin levels, the central satiety signal is blunted, leading to a paradoxical situation where appetite suppression is insufficient, yet overall food intake still declines due to other age‑related factors.
Interaction Between Ghrelin and Leptin in the Elderly
The balance between ghrelin and leptin is crucial for fine‑tuning energy intake. In younger adults, a high ghrelin/low leptin ratio signals energy deficit, prompting feeding, whereas a low ghrelin/high leptin ratio signals satiety. In older individuals, this ratio becomes less dynamic:
- Diminished ghrelin peaks reduce the “hunger push.”
- Leptin resistance weakens the “satiety brake,” but the overall drive to eat remains low because other age‑related cues (e.g., reduced taste perception, slower gastric emptying) dominate.
Experimental models demonstrate that restoring a more youthful ghrelin profile—through ghrelin agonists or GOAT activation—can partially rescue appetite in aged rodents, whereas leptin sensitizers improve energy expenditure without markedly increasing food intake. These findings underscore that therapeutic modulation of one hormone may need to be complemented by addressing the other to achieve balanced appetite regulation.
Implications for Energy Balance and Body Composition
The combined effect of altered ghrelin and leptin signaling contributes to a net negative energy balance in many older adults, predisposing them to:
- Sarcopenic obesity: Loss of lean muscle mass alongside modest fat gain, driven by reduced protein synthesis and altered lipid metabolism.
- Undernutrition: Progressive decline in caloric intake leading to weight loss, frailty, and increased morbidity.
- Metabolic dysregulation: Impaired glucose tolerance and insulin sensitivity, partly mediated by disrupted ghrelin‑insulin interactions.
Understanding the hormonal underpinnings helps explain why simple caloric restriction, often recommended for weight management, may be counterproductive in the elderly without concurrent strategies to preserve appetite and muscle mass.
Research Gaps and Future Directions
Although substantial progress has been made, several unanswered questions remain:
- Longitudinal hormone profiling: Most data are cross‑sectional; prospective studies tracking ghrelin and leptin trajectories alongside body composition changes would clarify causality.
- Sex‑specific patterns: Hormonal interplay may differ between older men and women, especially considering post‑menopausal estrogen decline and its impact on leptin signaling.
- Genetic and epigenetic modifiers: Polymorphisms in the GHSR and LEPR genes, as well as age‑related epigenetic modifications, could influence individual susceptibility to appetite dysregulation.
- Intervention trials: Controlled trials using ghrelin mimetics, GOAT activators, or leptin sensitizers in older populations are needed to assess efficacy, safety, and impact on functional outcomes such as muscle strength and quality of life.
- Integration with gut microbiota: Emerging evidence suggests that microbial metabolites can modulate ghrelin and leptin secretion; exploring this axis may uncover novel, non‑pharmacologic avenues for appetite support.
Addressing these gaps will refine our mechanistic understanding and pave the way for targeted, evidence‑based approaches that respect the delicate hormonal balance governing appetite in aging.
In summary, the age‑related attenuation of ghrelin secretion and the concurrent development of leptin resistance together reshape the appetite landscape in older adults. These hormonal shifts, interacting with broader physiological changes, underlie the reduced hunger signals and altered satiety perception that characterize aging. A nuanced appreciation of ghrelin and leptin dynamics is essential for researchers and clinicians seeking to develop interventions that maintain optimal energy balance and support healthy body composition throughout the later decades of life.
