SHLP (Small Humanin-Like Peptides)

Small Humanin-Like Peptides (SHLPs 1-6) are a family of mitochondrial-derived peptides encoded by the 16S ribosomal RNA region of mitochondrial DNA, each comprising 24-38 amino acids. These microproteins function as age-dependent regulators of cellular metabolism, apoptosis, insulin sensitivity, and inflammatory responses. SHLP2 and SHLP3 exhibit cytoprotective effects by enhancing mitochondrial function and reducing oxidative stress, while SHLP6 demonstrates opposing pro-apoptotic activity. Emerging research indicates these peptides play crucial roles in metabolic disorders, neurodegenerative diseases, and aging-related pathologies, with SHLP2 showing particular promise as a therapeutic target for obesity, diabetes, macular degeneration, and Parkinson's disease.

Metabolic and Energy Homeostasis

SHLP2 demonstrates potent effects on energy regulation by protecting mice from high-fat diet-induced obesity and improving insulin sensitivity through activation of pro-opiomelanocortin (POMC) neurons in the hypothalamus ^[1][3]. Both SHLP2 and SHLP3 function as insulin sensitizers, increasing peripheral glucose uptake and suppressing hepatic glucose production ^[2]. Treatment with SHLP2 and SHLP3 significantly increases oxygen consumption rate (OCR) and cellular ATP levels, indicating enhanced mitochondrial metabolism and biogenesis ^[2][8].

Neuroprotection and Age-Related Disease

SHLP2 provides protective effects against age-related macular degeneration by restoring oxidative phosphorylation complex protein levels, preventing cell loss, and reducing mitochondrial dysfunction in retinal cells ^[4][10]. A naturally occurring variant of SHLP2 (K4R) reduces Parkinson's disease risk by approximately 50% through enhanced binding to mitochondrial complex 1, preventing enzyme activity decline and protecting against neurotoxin-induced damage ^[5][11]. Both SHLP2 and humanin exhibit chaperone-like activity, directly inhibiting islet amyloid polypeptide (IAPP) misfolding at substoichiometric concentrations, offering potential therapeutic benefits for type 2 diabetes ^[6].

Cellular Cytoprotection and Anti-Aging

SHLP2 and SHLP3 significantly reduce cellular apoptosis and reactive oxygen species generation while enhancing mitochondrial health in various cell types including β-cells and prostate cells ^[2]. SHLP3 promotes adipocyte differentiation, mediates ERK signaling, and downregulates metabolic and inflammatory markers ^[2][8]. Circulating SHLP2 levels decline with age, and supplementation improves multiple metabolic markers associated with age-related disorders ^[2][9]. The peptides demonstrate tissue-specific expression patterns, with SHLP2 detected in liver, kidney, and muscle; SHLP3 in brain and spleen; suggesting targeted biological functions ^[2].

Biomarker and Diagnostic Potential

Low circulating SHLP2 levels serve as a novel biomarker for prostate cancer risk, with levels above 350 pg/mL ruling out prostate cancer with ≥95% accuracy in men undergoing biopsy ^[7]. Addition of SHLP2 to standard diagnostic models (age, PSA, race) improves predictive accuracy from 0.67 to 0.85 AUC for prostate cancer detection ^[7].

Molecular Mechanisms

SHLP2 binds to and activates chemokine receptor CXCR7 (ACKR3) with an EC50 of 0.97 μM, mediating its effects through MAPK-ERK pathway activation and β-arrestin recruitment ^[3]. The peptide demonstrates evolutionary conservation, with SHLP6 and humanin showing strong synonymous codon bias indicating natural selection, while SHLP1, SHLP2, SHLP3, and SHLP5 show less conservation ^[12].

Current Safety Profile

As endogenous mitochondrial-derived peptides naturally produced in human tissues, SHLPs are hypothesized to have favorable safety profiles, though formal comprehensive toxicology studies have not been extensively published ^[8]. The peptides are expressed across multiple human tissues including liver, kidney, muscle, brain, spleen, heart, and prostate, indicating physiological roles rather than pathological effects ^[2].

Preclinical Safety Data

Preclinical studies in mouse models demonstrate that both systemic and intracerebroventricular administration of SHLP2 are well-tolerated, with animals showing improved metabolic parameters without reported adverse effects ^[3][9]. Treatment with SHLP2 and SHLP3 in cell culture studies shows enhancement of cell viability and mitochondrial function without toxicity across multiple cell lines including NIT-1 β-cells, 22Rv1 prostate cells, and ARPE-19 retinal cells ^[2][4][6].

Considerations and Limitations

While peptide therapeutics generally raise greater concerns regarding administration-related reactions than intrinsic peptide toxicity, specific safety data for exogenous SHLP administration in humans is currently unavailable ^[8]. No clinical trials evaluating SHLP safety or efficacy in humans have been reported to date, limiting conclusions about therapeutic safety profiles ^[8]. SHLP6 demonstrates pro-apoptotic rather than cytoprotective effects, significantly increasing apoptosis in tested cell lines, suggesting this family member may have different safety considerations ^[2].

Developmental Status

SHLP peptides remain in preclinical research stages with no active clinical trials registered. The related mitochondrial-derived peptide MOTS-c analog (CB4211) has entered clinical trials for metabolic disorders (NCT03998514), potentially providing a regulatory pathway framework for future SHLP therapeutic development ^[8]. Standard preclinical toxicology assessments including dose-response studies, reproductive toxicity, genotoxicity, and long-term safety evaluations would be required before human trials, following FDA guidance for biotechnology-derived products ^[8].