SHLP-2 (Small Humanin-Like Peptide 2)

SHLP-2 (Small Humanin-Like Peptide 2) is a 12-amino acid mitochondria-derived peptide (MDP) encoded within the 12S ribosomal RNA (mt-RNR1) gene of the mitochondrial genome. It is part of the growing family of mitochondrial-derived peptides — small bioactive peptides encoded within the mitochondrial genome in regions previously thought to be non-coding.

The MDP family was pioneered by Pinchas Cohen's laboratory at the USC Leonard Davis School of Gerontology. Humanin (HN) was the founding member, discovered in 2001 as a 21-amino acid peptide neuroprotective against Alzheimer's-related neuronal death. SHLP-1 through SHLP-6 were subsequently identified from the same mt-12S rRNA region.

**SHLP-2 vs Humanin:** Both are encoded within the same 12S rRNA mitochondrial locus and have similar but distinct sequences. In direct comparison studies, SHLP-2 demonstrated 3-10x greater potency than humanin in blocking beta-amyloid peptide (Aβ25-35 and Aβ1-42)-induced neuronal apoptosis in SH-SY5Y and primary cortical neuron cultures. The greater potency of SHLP-2 at lower concentrations makes it a more interesting research tool.

**Mechanisms of action:** - **Mitochondrial ROS reduction**: Reduces superoxide generation in the mitochondrial electron transport chain; protects against Complex I dysfunction - **Anti-apoptotic**: Inhibits cytochrome c release and caspase-3 activation in response to amyloid and other apoptotic stimuli - **Metabolic effects**: SHLP-2 reduces de novo lipogenesis in adipocytes (downregulates FASN, ACC1) — potentially beneficial for obesity and metabolic syndrome - **Signaling**: Proposed to interact with formyl peptide receptor-like 1 (FPRL1) similar to humanin, activating STAT3 and PI3K/Akt pro-survival pathways

**Aging biomarker:** A cross-sectional study of 134 men from the Baltimore Longitudinal Study of Aging (Cobb et al., 2016) found that circulating SHLP-2 levels inversely correlated with chronological age and positively correlated with various health and vitality measures. Diabetes, cardiovascular disease, and frailty were associated with lower circulating SHLP-2, suggesting it as a potential longevity biomarker.