SHLP1 (Small Humanin-Like Peptide 1)
SHLP1 is a mitochondria-derived micro-peptide encoded by the 16S rRNA region of the mitochondrial genome with anti-apoptotic and cytoprotective properties, showing research promise in neurodegeneration, metabolic regulation, and aging.
SHLP1 (Small Humanin-Like Peptide 1) is a mitochondria-derived peptide (MDP) encoded by a short open reading frame within the 16S rRNA gene of the mitochondrial genome — the same region that encodes humanin. Identified through bioinformatic screening of the mitochondrial transcriptome, SHLP1 exhibits anti-apoptotic and cytoprotective properties that parallel those of humanin, though with distinct tissue distribution and potency profiles.
Overview
SHLP1 belongs to a family of six small humanin-like peptides (SHLP1–6) discovered in 2016 by Cobb and colleagues at the University of Southern California. These peptides were identified through systematic analysis of all possible short open reading frames (sORFs) within the mitochondrial 16S rRNA gene — the same gene that encodes humanin, the founding member of the mitochondria-derived peptide family. SHLP1 shares the anti-apoptotic orientation of humanin and most other SHLPs (with the notable exception of SHLP6, which is pro-apoptotic), protecting cells from stress-induced programmed cell death. Circulating SHLP1 levels decline with age in parallel with other MDPs, correlating with increased susceptibility to neurodegenerative disease and metabolic dysfunction.
Mechanism of Action
SHLP1 exerts cytoprotective effects primarily through inhibition of mitochondrial apoptosis pathways. Like humanin, SHLP1 interferes with the Bcl-2 family-mediated apoptotic cascade, preventing the release of cytochrome c from mitochondria and subsequent caspase activation. The peptide modulates mitochondrial membrane potential stability under stress conditions, preserving organelle integrity when cells are exposed to oxidative damage, amyloid-beta toxicity, or metabolic insults (Cobb et al., 2016).
SHLP1 signals through pathways that partially overlap with humanin but are not identical. While humanin primarily engages the FPRL1/FPRL2 receptors and the trimeric CNTFR/WSX-1/gp130 complex to activate STAT3 signaling, SHLP1 appears to engage distinct receptor systems that remain under investigation. The peptide activates ERK1/2 signaling and modulates AKT phosphorylation, both of which contribute to cell survival and proliferation. SHLP1 also reduces reactive oxygen species (ROS) production in stressed cells, suggesting a role in mitochondrial quality control beyond direct anti-apoptotic activity.
Importantly, SHLP1 has been shown to interact with amyloid-beta oligomers in vitro, potentially reducing their aggregation and neurotoxicity. This interaction places SHLP1 in the category of endogenous neuroprotective factors that decline during Alzheimer's disease pathogenesis, contributing to the vulnerability of neurons to plaque-induced apoptosis (Kim et al., 2018).
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Research
Alzheimer's Disease Research
SHLP1 has shown neuroprotective properties in models of Alzheimer's disease pathology. In primary cortical neuron cultures exposed to amyloid-beta 1-42 oligomers, SHLP1 treatment improved cell viability in a dose-dependent manner (Kim et al., 2018). The peptide reduced amyloid-beta-induced mitochondrial fragmentation and preserved dendritic spine density, suggesting protection of both cell survival and synaptic function.
The neuroprotective effect of SHLP1 against amyloid-beta toxicity parallels that of humanin, though with lower potency. While humanin analogue HNG protects neurons at picomolar concentrations, SHLP1 requires nanomolar to low micromolar concentrations for equivalent protection. However, the additive or synergistic effects of multiple MDPs — each declining with age — may be more physiologically relevant than individual peptide potency.
Metabolic Regulation
SHLP1 contributes to metabolic homeostasis through mechanisms that partially overlap with SHLP2 and humanin. In adipocyte cell cultures, SHLP1 modulates lipid metabolism and reduces lipid accumulation under high-glucose conditions. The peptide enhances insulin receptor substrate (IRS) phosphorylation and downstream PI3K/AKT signaling, improving cellular insulin sensitivity (Cobb et al., 2016).
Animal studies have demonstrated that exogenous SHLP1 administration improves glucose tolerance in diet-induced obesity models. Mice receiving SHLP1 by intraperitoneal injection showed reduced fasting glucose and improved insulin sensitivity as measured by homeostatic model assessment (HOMA-IR), though the metabolic effects of SHLP1 were less pronounced than those observed with SHLP2.
Apoptosis Protection
The foundational discovery of SHLP1 by Cobb et al. (2016) demonstrated that the peptide protects cells from serum starvation-induced apoptosis in vitro. In mouse embryonic fibroblasts and neuronal cell lines, SHLP1 treatment reduced caspase-3/7 activation by approximately 30–40% compared to untreated controls. The anti-apoptotic effect was dose-dependent and could be partially blocked by ERK inhibitors, confirming the involvement of MAPK signaling in SHLP1-mediated protection.
Further work established that SHLP1 protects mitochondrial membrane potential under conditions of oxidative stress. When cells were exposed to hydrogen peroxide or tert-butyl hydroperoxide, SHLP1 pre-treatment preserved mitochondrial transmembrane potential (ΔΨm) and reduced cytochrome c release into the cytoplasm. This protective effect was observed across multiple cell types including neurons, cardiomyocytes, and hepatocytes, suggesting broad cytoprotective relevance.
Age-Related Decline
Circulating SHLP1 levels decline significantly with age in both mice and humans, mirroring the decline pattern observed for humanin, SHLP2, and MOTS-c. Kim et al. (2018) demonstrated that plasma SHLP1 concentrations are approximately 50% lower in individuals over 65 compared to those under 35. This decline correlates with reduced mitochondrial DNA copy number and impaired mitochondrial transcription, suggesting that age-related mitochondrial dysfunction reduces production of the entire MDP family.
Safety Profile
SHLP1 is an endogenous peptide produced naturally by mitochondria in all nucleated human cells. As a native biological molecule, it operates within established physiological pathways. Exogenous administration in cell culture and animal models has not produced significant adverse effects at research doses. The primary theoretical concern mirrors that of humanin: anti-apoptotic peptides could theoretically promote survival of pre-cancerous cells by blocking programmed cell death. However, this has not been demonstrated in SHLP1 research to date, and the peptide's relatively modest potency compared to humanin analogues may limit this risk. Human clinical data are not yet available.
Pharmacokinetic Profile
- Half-life
- Not established in humans
Quick Start
- Typical Dose
- 250mcg
- Route
- Subcutaneous injection
- Storage
- Refrigerate 2-8°C
Research Protocols
subcutaneous Injection
Subcutaneous injection
Interactions
Peptide Interactions
While humanin analogue HNG protects neurons at picomolar concentrations, SHLP1 requires nanomolar to low micromolar concentrations for equivalent protection.
MOTS-c activates AMPK and drives metabolic optimization, while SHLP1 provides cytoprotective signaling. Combining metabolic enhancement (MOTS-c) with apoptosis resistance (SHLP1) could address the dual challenge of aging: declining energy metabolism and increased cell death.
SHLP2 has stronger metabolic effects, particularly on adipocyte differentiation and insulin sensitivity. Combining SHLP1's cytoprotective focus with SHLP2's metabolic benefits may provide broader anti-aging coverage than either peptide alone.
What to Expect
What to Expect
Following subcutaneous or intraperitoneal injection in rodent models, SHLP1 reaches peak plasma concentration within 30–60 minutes.
Age-stratified studies show that older animals (18–24 months in mice) have significantly lower circulating SHLP1 and respond more robustly to...
Continued use as directed
Quality Indicators
What to look for
- Human clinical trials conducted
- Naturally occurring compound
- Multiple peer-reviewed studies available
Caution
- Limited human data available
Frequently Asked Questions
References (10)
- [3]Yen et al The emerging role of the mitochondrial-derived peptide humanin in stress resistance J Mol Endocrinol (2020)
- [9]Yen et al — Mitochondrial-derived peptides as novel regulators of metabolism and aging Cell Metab (2023)
- [10]Miller et al — Small humanin-like peptides: expanding the mitochondrial-derived peptide landscape Trends Endocrinol Metab (2023)
- [12]Kim et al — Humanin and its analogs as therapeutic targets for age-related diseases Ageing Res Rev (2023)
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- [5]Zhai et al Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak J Biol Chem (2005)
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- [2]
- [8]
- [7]Hashimoto et al Humanin inhibits apoptosis through interaction with IGFBP-3 Neurosci Lett (2009)
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