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Hedi Raizer

Journal 7 min read

How Metabolic Adaptation Changes with Age

Metabolic adaptation is the coordinated shift in fuel handling, endocrine signalling and mitochondrial function that follows a change in nutrient supply. This page reviews what laboratory and clinical studies report abou

peptides-pro Editorial

Metabolic adaptation is the umbrella term for the coordinated set of shifts in substrate handling, endocrine signalling and mitochondrial function that a tissue mounts when nutrient supply, energy demand or protein source changes. Synonyms in the literature include adaptive metabolic response, metabolic flexibility and, in the dietary-restriction literature, the adaptive thermogenesis response. The term is a physiological descriptor rather than a defined molecular entity, so it carries no sequence, formula or molecular weight; the identifiers in this literature belong to the individual mediators studied, such as the mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c) peptide and the small humanin-like peptides SHLP1-6, which are encoded by small open reading frames within mitochondrial DNA [7].

The work reviewed here centres on the mitochondrial-derived peptide family and its downstream nuclear-receptor and endocrine signalling, particularly the REV-ERB arm of the circadian nuclear receptor family and the FGF21 co-receptor axis [6][7][12].

Research Studies

Liver glutamate dehydrogenase and dietary protein source in mice

Control mice and Hep-Glud1-/- mice lacking liver glutamate dehydrogenase (GDH) were fed either animal-based or plant-based diets for four days while total macronutrient spectrum was held constant. Hepatic GDH was upregulated in control mice eating animal proteins relative to mice on the plant regimen, and ad libitum fed control mice showed lower glycemia under the plant-based regimen than under the animal-based one. The authors concluded that the transition to dietary plant-based proteins requires functional liver GDH for proper control of ammonia and energy homeostasis [1]. This is a mouse study; no equivalent human dietary-switch dataset is reported in the evidence reviewed here.

Hepatic proteomic recovery after refeeding in Japanese quail

Eighteen 12-week-old male Japanese quail (Coturnix japonica), mean body mass 245.20 ± 0.213 g, were assigned to three groups of six: ad libitum control fed a 12.13 MJ/kg diet, 24 h feed deprivation followed by 6 h refeeding, and 24 h on a low metabolizable energy diet (6.30 MJ/kg) followed by 6 h refeeding. Of 854 proteins identified, 515 met the study's filter criteria, and the authors characterised early hepatic protein signatures during recovery from nutritional stress [3]. The design is avian and the refeeding window is six hours, so the findings describe a rapid hepatic proteomic response rather than a chronic adaptation.

Low-protein diet, FGF21 and the gut microbiota in chronic kidney disease

Low-protein diets are recommended in chronic kidney disease to slow progression, but their clinical efficacy and safety are debated because of the risk of protein-energy wasting. In murine models and in a randomized controlled trial in nondiabetic CKD patients, the low-protein diet improved glucose tolerance and significantly decreased circulating gut-derived uremic toxins while reducing body weight by 33% in the experimental setting. The authors attributed the effect to inhibition of an FGF21 adaptive stress response, with gut microbiota remodelling and endocrine adaptation as co-mechanisms [4].

Adipose FGF21 signalling and protein restriction

Dietary protein restriction is a recognised nutritional intervention that improves metabolic health and extends lifespan, and the mechanism has been incompletely understood. Using genetic loss-of-function models for fibroblast growth factor 21 and its obligate co-receptor, this work reports that adipose FGF21 signalling mediates the anti-senescence effects of protein restriction [12]. The finding is from genetic models and is reported here as a mechanism, not as a human intervention result.

REV-ERB agonism and sorafenib in liver cancer models

Genome-wide RNA-seq analysis in hepatocellular carcinoma identified mitochondrial oxidative phosphorylation and Hmox1 upregulation as features of the disease. On that basis, the REV-ERB agonist SR9009 was tested as a potentiator of sorafenib efficacy, with the authors framing the approach as targeting metabolic vulnerabilities [6]. This is a preclinical therapeutic strategy; the evidence block does not report a human trial of the combination.

Mitochondria-derived peptides in hepatic metabolism

Humanin, the first mitochondria-derived peptide described, functions as a cytoprotective factor that protects cells from stress-induced apoptosis. The family was subsequently expanded to include MOTS-c, described as a key regulator of metabolic homeostasis and stress adaptation, and SHLP1-6, which modulate mitochondrial bioenergetics and insulin sensitivity. Intracellularly, these peptides modulate mitochondrial function, and the review positions them as emerging regulators of hepatic metabolism and therapeutic targets in liver disease [7].

HLA-G as a tumour-intrinsic driver in renal cell carcinoma

HLA-G is a non-classical MHC class I molecule with immunoregulatory functions that is aberrantly expressed in multiple malignancies. In clear cell renal cell carcinoma, analysis of the Cancer Genome Atlas cohort showed that elevated HLA-G expression was associated with immunosuppressive programmes and cell populations, and interrogation of a public single-cell RNA sequencing dataset showed that HLA-G expression within tumour epithelial clusters was associated with hypoxia-related programmes. The authors used integrated transcriptomic, in vitro and in vivo approaches and concluded that HLA-G functions as a tumour-intrinsic driver of growth and survival [2].

Carotenoid biosynthesis and stress sensitivity in Cordyceps militaris

Cordyceps militaris produces orange-yellow fruiting bodies largely through carotenoid accumulation. Cmpks1, a light-induced gene encoding a reducing type I polyketide synthase, was identified as a key regulator of pigment biosynthesis; its transcription was CmWC-1-dependent and upregulated during fruiting body development. CRISPR/Cas9 loss-of-function mutants showed stable albino phenotypes while retaining fruiting body differentiation, and disruption of Cmpks1 increased sensitivity to high-stress conditions in addition to abolishing carotenoid biosynthesis [5]. This is a fungal model system.

Age-related and intervention-related comparisons

Several lines of evidence compare metabolic markers across age or across weight-cycling and surgical interventions, but they are reported here as reference material rather than as the page's core content. A comparative study characterised adipokine profiles in middle-aged master athletes, untrained adults and young individuals, noting that adipose tissue is an active endocrine organ whose regulatory and inflammatory processes are altered during aging [9]. A review examined exerkine-mediated inter-organ crosstalk, arguing that the systemic benefits of exercise cannot be fully explained by increased energy expenditure, enhanced skeletal muscle glucose uptake, reduced adiposity or improved peripheral insulin sensitivity alone [10]. A preliminary study evaluated early postoperative changes in the energy-regulating hormones irisin and nesfatin-1 after laparoscopic sleeve gastrectomy in women with obesity, in order to characterise early hormonal contributions to metabolic adaptation [11]. A registered trial is evaluating a probiotic preparation in weight cyclers, on the rationale that weight regain after caloric restriction is common because of metabolic adaptation and that gut microbiota influence weight management [8].

Model or populationAdaptive variable measuredDirection reported
Mice, control vs Hep-Glud1-/-, 4-day diet switch [1]Hepatic GDH, glycemiaGDH upregulated on animal protein; lower glycemia on plant regimen in controls
Japanese quail, 24 h deprivation or low-energy diet then 6 h refeeding [3]Hepatic proteome (854 proteins identified, 515 filtered)Early recovery signatures characterised
Murine models and nondiabetic CKD patients on low-protein diet [4]Glucose tolerance, uremic toxins, body weightImproved tolerance, decreased toxins, −33% body weight in the experimental setting
Genetic Fgf21 loss-of-function models under protein restriction [12]Adipose FGF21 signalling, senescenceAdipose FGF21 signalling mediates anti-senescence effects

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