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. 2025 Nov 26;11(1):104. doi: 10.1038/s41514-025-00292-3

Simple molecules make difference: short peptides play a novel role in slowing senescence

Ya Li 1,#, Xiangzhan Zhu 2,3,#, Pengya Feng 4,#, Chunjing Qiu 1, Xia Xue 1,✉, Xiangdong Sun 1,✉
PMCID: PMC12722213  PMID: 41298538

Abstract

Aging studies have entered a transformative era with the discovery and application of short peptides as regulators of senescence. These short peptides are encoded by small open reading frames in nuclear, mitochondrial, and viral genomes. Unlike non-coding RNAs, short peptides are evolutionarily conserved and play a role in ameliorating decline of cellular function. It has now been recognized involved in nearly all biological processes, including diseases and senescence, however, the mechanisms behind it are complicated and largely unexplored. This review aims to summarize the evidence that short peptides slow senescence by targeting interactions with core aging hallmarks in animals. The cross-species studies were reviewed from nematodes to mammals, in which short peptides can modulate the aging-related targets precisely, such as sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) pumps and Bcl-2-associated X protein complexes. In parallel, the disorder of these short peptides accelerates age-related pathologies, while therapeutic administration extends healthspan in different animal models. Short peptides achieve disproportionate biological functions while challenges remain in peptide detection, delivery, and mechanistic decoding, yet engineered variants and gene therapies hold promise for clinical translation. By bridging molecular simplicity with systemic resilience, short peptides redefine strategies for healthy aging.

Subject terms: Biochemistry, Biological techniques, Computational biology and bioinformatics, Systems biology

Introduction

Regardless of its controversy, “being immortal” is an attractive and long-term study along the history of our civilization. For all animals on Earth, aging is an irreversible biological process that characterized by the gradual decline of cellular function, leading to tissue degeneration and increased susceptibility to disease1–3. It is normally caused by the accumulation of damage in response to different inner and environmental stressors during individuals’ life-long time4 (Fig. 1). In last century, it has been found that the strong light intensity can increase the lifespan of Drosophila5,6. The temperature and elemental stoichiometric alternation (e.g., Phosphorus) can impact the growth and reproduction rate of nematodes (Caenorhabditis elegans (C. elengans) and Plectus murrayi)7,8. In parallel, caloric restriction has been confirmed to be related to health statues and longevity in mice and rats9. These findings suggest the plasticity of the aging process is a key factor to healthspan, even the longevity in most animals. Since the first long-lived C. elengans strain has been isolated, scientists realize that aging can be studied and plays a causality of various disorders in humans, including cardiovascular disease, diabetes, Alzheimer’s disease, Parkinsons’s disease, and other physical disorders10. Particularly after the age of 60 years, patients with advanced age usually need combinations of different treatments to keep their health status11. Therefore, it is important to understand the aging process and its related disease, as well as develop novel strategies or agents suitable for extending the healthspan in humans.

Fig. 1. The hallmarks of aging, including cellular senescence (cell aging), energy loss (mitochondrial dysfunction/metabolic decline), chronic inflammation (inflammaging), genomic/chromosomal instability, and gene regulation disorder.

Fig. 1

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This schematic summarizes key biological hallmarks associated with aging and illustrates how they interact to drive tissue dysfunction and disease susceptibility.

Most traditional research has focused on well-established pathways involving DNA damage, telomere attrition, oxidative stress, and macromolecular dysfunction. Recently, short peptides have been found in studies as a surprising class of regulators, which are now emerging as critical, non-canonical modulators of longevity and senescence12. The conventional proteome has largely focused on long, well-annotated proteins, yet advances in genomics, ribosome profiling, and proteomics have uncovered a vast repertoire of functional short proteins translated from transcripts previously deemed “non-coding”13. These molecules defy their simplicity, exhibiting potent, targeted roles in essential processes such as mitochondrial function, stress response, apoptosis, and metabolic regulation14,15. Their dysregulation strongly correlates with accelerated senescence, while their targeted enhancement shows promise in extending healthspan in animals from simple to complex ones16,17. This work reviewed the role of short peptides as novel agent to improve the health status against cellular decline along with aging. We explored their mechanisms from modulating oxidative stress and sustaining proteostasis to drive nutrient-sensing networks, and highlighted specific short peptides with demonstrable anti-senescence effects. We further discussed their therapeutic potential, challenges in discovery and validation, and the paradigm shift they represent in aging biology. By bridging molecular simplicity with profound functional impact, short peptides offer whole new insights for developing targeted anti-aging interventions.

The short peptides

Short peptides are the mini peptides usually smaller than 100 amino acids, including some oligopeptides (opioids, cyclic peptide penicillin, and polypeptide insulin) with only 2–10 amino acids. Due to genomic annotation bias and technical limitation, short peptides have been underestimated for a long time. This “dark proteome” is abundant in cells and once dismissed as transcriptional “noise” or non-functional byproducts18. Advances in ribosome profiling, mass spectrometry, and bioinformatics have identified thousands of conserved short proteins translated from small open reading frames (sORFs) in both annotated genes and non-coding RNAs19–21. These simple biomolecules have been found as critical regulators across most biological processes, and their non-toxic and unique properties bring them a great potential in anti-aging strategy and lower the concurrence of aging-related disorder. Moreover, the discovery of these short peptides represents a paradigm shift, revealing a hidden layer of proteomic complexity and expanding the functional landscape of the genome22.

Since the first peptide hormone oxytocin has been widely used in 90 s, oligopeptides are confirmed to be significant in drug development. Their capability of tissue repair through enhancing cell proliferation and cell-cell interactions makes short peptides are star biomolecules for against skin aging. Bioactive peptides can be categorized as signal peptides, carrier peptides, neurotransmitter-inhibiting peptides based on their functions (Table 1). They localize to critical compartments (e.g., mitochondria, endoplasmic reticulum, nucleus) and engage in modulating enzyme activity, altering membrane dynamics, or serving as signaling ligands. For instance, mitochondrial-derived peptides such as Humanin and MOTS-c regulate metabolism and stress responses by interacting with IGF-1 and AMPK pathways, while endoplasmic reticulum-resident micropeptides such as PIGBOS modulate ER-mitochondrial crosstalk to control apoptosis. Others, like the iron-regulatory myoregulin, directly inhibit SERCA pumps in muscle. This mechanistic versatility enables short peptides to influence development, immunity, metabolism, and cellular homeostasis with remarkable specificity.

Table 1.

The categories of the short peptides

Type Examples Size(aa) Origin resource Mechanism Aging-related role Refs
Micropeptides Humain 24 Mitochondrial 16S rRNA Inhibit apoptosis; activates FPR2 to reduce inflammation Protects neurons, reduces oxidative stress 73,74
MOTS-c 16 Mitochondrial 12S rRNA AMPK activation via folate cycle disruption; regulates glucose metabolism Improves insulin sensitivity, slow muscle senescence 75
Peptide Hormones FGF21 181 Secreted by liver/adipose PPARα/PGC-1α pathway activation Promotes autophagy, extends mouse lifespan 76
Ghrelin 28 Stomach (proteolytic cleavage of preproghrelin) Agonist for GHSR AMPK/mTOR modulation Stimulates appetite, preserves muscle mass 77
Antimicrobial peptides LL-37Cathelicidin 37 Immune cells (cleaved from hCAP18) Disrupts microbial membranes; binds CXCR2/TLR4, activates autophagy Reduce immunosenescence and chronic inflammation 78
Proteolytic fragments Amyloid-β (Aβ42) 42 Amyloid Precursor Protein (APP) cleavage by β/γ-secretase Forms neurotoxic oligomers, Ca²⁺ dyshomeostasis, synaptic loss Drives Alzheimer’s pathology; accumulates with age due to reduced proteostasis 79
C-terminal Agrin Fragment (CAF) 22/90 Agrin cleavage by neurotrypsin at NMJ Inhibits LRP4/MuSK signaling destabilizes neuromuscular junctions Causes sarcopenia; serum CAF levels correlate with muscle aging 80,81
Chaperone peptides HSP27 205 Induced by HSF1 under stress Binds misfolded proteins via α-crystallin domain, inhibits apoptosome. Maintains proteostasis, extends C. elegans lifespan 82,83
Bioactive cryptides Hemopressin 9 Hemoglobin α-chain (proteolytic cleavage) Inverse agonist of CB1 receptor, modulates nociception Regulates neuroinflammation; potential role in combating age-related pain disorders 84,85
Ku70-derived peptide 5 Ku70 (DNA repair protein) cleavage Blocks Bax translocation to mitochondria, inhibits apoptosis. Lower DNA damage-induced cell death; overexpression rescues age-related neuronal loss 86,87
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The dysregulation of short peptides is increasingly linked to human diseases, underscoring their translational relevance. In cancer, micropeptides like CASIMO1 drive proliferation23, while noBody (non-annotated P-body dissociating polypeptide) regulates mRNA decay and tumor suppression24. In cardiometabolic disorders, peptides such as dwarf open reading frame (DWORF) enhance cardiac contractility, offering therapeutic alternatives to conventional drugs25. Their small size, tissue-specific expression, and low immunogenicity make them attractive candidates for peptide-based therapeutics or gene therapies. As tools like CRISPR screening and single-cell omics accelerate their discovery, short proteins are poised to redefine molecular understanding across disease models, bridging fundamental biology with clinical innovation.

The roles of short peptides in aging and intercellular signaling

Short peptides originating from nuclear or cytoplasmic genomic regions represent a paradigm-shifting class of regulators. Translated from upstream open reading frames (uORFs), untranslated regions (UTRs), or non-coding RNAs (e.g., long non-coding RNAs, circular RNAs), these micropeptides are involved in cellular processes with remarkable precision. For instance, uORF-encoded peptides modulate ribosome scanning to control translation of downstream main ORFs26,27, while peptides like CYREN promote DNA repair by regulating Ku complex activity28,29. Non-coding RNA-derived species, such as PUNISHER in Drosophila, orchestrate neuronal development through targeted protein interactions30,31.

Mitochondria and secretory organelles harbor evolutionarily conserved short peptides critical for cellular homeostasis. Mitochondrial-derived peptides (MDPs), encoded by mitochondrial DNA (mtDNA) sORFs, include potent metabolic regulators like MOTS-c (16 aa), which activates AMPK to enhance glucose metabolism and oxidative stress resistance32, and Humanin (24 aa), a cytoprotective agent that suppresses apoptosis by inhibiting BAX33. Similarly, endoplasmic reticulum (ER)-localized micropeptides such as PIGBOS (54 aa) maintain proteostasis by tethering ER-mitochondria contact sites, while Golgi-resident RIC1 controls vesicular trafficking34. These organelle-specific peptides act as sentinels against senescence by sustaining energy production, reducing proteotoxic stress, and preventing organelle dysfunction—a hallmark of aging35.

Despite diverse origins, short peptides converge on core pathways governing aging. Metabolic regulators (e.g., MOTS-c)36, ion channel modulators (e.g., myoregulin)37, and organelle communicators (e.g., PIGBOS) sustain mitochondrial function34, proteostasis, and calcium signaling. These processes are universally disrupted in senescence. Their efficiency stems from structural minimalism, for example myoregulin’s 46 aa precisely inhibit SERCA without off-target effects38, while MOTS-c’s 16 aa allosterically regulate AMPK39. This targeted functionality, paired with evolutionary conservation and tissue-specific expression, positions certain short proteins as master regulators of healthspan in animals. Their discovery challenges the “size-function” dogma, revealing that molecular simplicity can drive complex anti-senescence outcomes (Fig. 2)40,41.

Fig. 2.

Fig. 2

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The mechanisms of the short proteins on human health (Zhao et al., 2024).

Novel functions of short peptides on multiple aging models

Studies in C. elegans and Drosophila have been instrumental in uncovering evolutionarily conserved roles for short proteins in aging. In C. elegans, MDPs like MOAG-4 (orthologous to human MOTS-c) extend lifespan by over 20% via AMPK-dependent metabolic reprogramming42, while the 28-aa peptide ALP-1 (encoded by an sORF in the alh-6 gene) suppresses protein aggregation in aged neurons43. Similarly, Drosophila micropeptides such as Imp-L2 (68 aa), secreted from glia, modulate insulin/IGF signaling across tissues, delaying muscle senescence44.

In mammals, tissue-specific micropeptides regulate aging hallmarks with surgical precision. Skeletal muscle expresses myoregulin (46 aa) and DWORF (34 aa), which competitively regulate SERCA pump activity to maintain calcium homeostasis, preventing age-related atrophy37,45. In the brain, the astrocyte-enriched peptide PEPC7 (29 aa) reduces neuroinflammation by inhibiting NF-κB translocation46, while cardiac-specific ATGLp (71 aa) regulates lipolysis to preserve metabolic flexibility in aging hearts. Notably, gut-derived peptide hormones like GLP-1 (glucagon-like peptide-1; 30–31 aa), traditionally recognized for glucose regulation, now emerge as potent systemic modulators of aging. GLP-1 receptor agonists extend lifespan in mice, delay cognitive decline, and reduce senescent cell burden in multiple tissues47. GLP-1 signaling enhances hippocampal neurogenesis, suppresses systemic inflammation via gut-brain axis communication, and improves mitochondrial function in aged organs48. Also, many function through non-canonical pathways, such as MOTS-c (16 aa) translocates to nuclei in senescent cells, directly repressing pro-aging transcription factors like NFAT49.

Beyond animals, plants and pathogens showcase the ecological versatility of micropeptides. Arabidopsis expresses ROTUNDIFOLIA4 (RTF4; 53 aa), which interacts with brassinosteroid receptors to delay leaf senescence under drought stress50,51. Fungal pathogens like Candida albicans secrete Candidalysin that accelerates host cell senescence to promote invasion10. Conversely, plant defense micropeptides (e.g., GmPep914, 8 aa) trigger reactive oxygen species (ROS) scavenging in soybeans to counteract senescence during infection52. Secreted micropeptides function as endocrine or paracrine signaling molecules. Muscle-derived DWORF (34 aa) enhances cardiac contractility by activating SERCA pumps, while Enkurin (70 aa) regulates sperm fertility through TRPC channel binding53. Conversely, pathogen-encoded micropeptides reveal intriguing host-pathogen dynamics: viral genomes express peptides like KSHV-ORF52 that evade immune detection by downregulating MHC-I, and bacterial microcins (e.g., microcin E492) eliminate competitors via pore formation54,55. Dysregulation of endogenous secretory peptides correlates with cardiometabolic disease and infertility56,57, while pathogen-derived variants offer insights into antimicrobial design55. In addition, in chronic atrophic gastritis (AG), an aging condition initiated by Helicobacter pylori infection, a novel therapeutic secretory peptide has emerged. A natural peptide derived from traditional Chinese medicine was shown to revitalize atrophic epithelia and organoids by activating gastric stem cells (GSCs), functioning through stabilization of the EGF-EGFR complex and selective activation of ERK/Stat1 signaling58. These cross-kingdom examples confirm that short peptides have been co-opted for niche-specific survival strategies, positioning them as universal modulators of life-death balance in response to environmental stress.

Tissue-targeted short peptides in aging organs

Short peptides converge on conserved organ-specific pathways to delay tissue degeneration. The calcium-regulating micropeptide myoregulin (46 aa) maintains skeletal muscle function in mammals by inhibiting SERCA pump59, a role paralleled by Drosophila’s sarcolamban (55 aa), whose overexpression prevents age-related locomotor decline60. In the cardiovascular system, the cardiac micropeptide DWORF (34 aa) enhances contractility in aging mice by displacing SERCA inhibitors61, its functional analogue in zebrafish, smyhc1 (41 aa), similarly prevents heart failure via calcium handling62. Even in plants, the 53-aa peptide RTF4 in Arabidopsis delays leaf senescence by modulating brassinosteroid signaling63, akin to how human ELABELA (32 aa) promotes vascular health through angiotensin receptor signaling64. Some short peptides involved in collagen synthesis through fibroblasts can act as growth factors activating kinase C to enhance cell growth and migration65,66. These signal peptides, such as palmitoyl oligopeptide and Pentapeptide3, have been reported to slow the skin aging and promote skin firmness and youth-looking67,68 (Fig. 3). These molecules exemplify how minimalistic sequences can govern genome integrity, stress responses, and cell fate.

Fig. 3. The anti-aging function of short peptides in multiple organs.

Fig. 3

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The examples of short peptides in heart, skeletal muscle, and skin.

From microbes to mammals, short peptides counteract senescence induced by environmental stressors. In soybeans, the 8-aa peptide GmSubPEP scavenges ROS during drought, delaying leaf senescence69, which homologous with human MOTS-c in mitigating exercise-induced oxidative stress in muscle70. Candida albicans secretes the 31-aa cytolytic peptide candidalysin, accelerating host cell senescence to breach barriers, while beneficial bacteria produce micropeptides like lactococcin A (55 aa) that extend lifespan in C. elegans by suppressing competing pathogens71. Notably, even viral micropeptides manipulate host senescence pathways to enable latent persistence. This functional convergence highlights short proteins as a primordial toolkit for stress adaptation, repurposed across evolution to regulate life-death balance.

These cross-species parallels reveal a fundamental biological truth that short peptides achieve maximal functional impact through structural economy. Their small size enables rapid diffusion (e.g., MOTS-c crossing blood-brain barriers)72, precise binding in sterically constrained niches (e.g., myoregulin’s SERCA interaction)56, and low biosynthetic cost, advantages critical for combating senescence. While kingdom-specific adaptations exist (e.g., RTF4 in plants vs. Humanin in mammals)63, all leverage motifs targeting conserved aging pillars, including mitochondrial integrity, proteostasis, and stress signaling. This universality positions them as ideal blueprints for anti-aging therapeutics, with engineered variants already showing cross-species efficacy in preclinical models (Table 2).

Table 2.

The short peptides from different organisms on aging research

Organisms Short peptides Senescence targets Effect Refs
Caenorhabditis elegans MOAG-4/MOTS-c AMPK/Mitochondrial biogenesis Increase lifespan, reduce protein aggregation 42
Mouse/Human Humanin IGF-1/BAX signaling Blocks neuronal apoptosis 33
Drosophila Sarcolamban SERCA calcium pumps Prevent muscle degeneration 56
Arabidopsis RTF4 Brassinosteroid receptors Delay drought-induced aging 63
Soybean GmSubPeP ROS Suppress oxidative senescence 69
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Conclusion and prospectus

The study of short peptides marks a paradigm shift in aging research from viewing senescence as an inevitable cascade of damage to recognizing it as a dynamically regulated process, regulated by short peptides. This review discussed evidence that short peptides encoded in nuclear, mitochondrial, and viral genomes are conserved, potent modulators of aging-related pathways. We summarized origins (uORFs, lncRNAs, circular RNAs, mtDNA sORFs), representative examples (MOTS‑c, Humanin, myoregulin/DWORF, CYREN, PIGBOS), and cross‑species functions from invertebrates to mammals showing these peptides tune mitochondrial bioenergetics, proteostasis, Ca2+ handling, DNA repair, and apoptotic thresholds. Short peptides act through recurring motifs, direct binding and modulation of protein complexes, allosteric activation of signaling enzymes, organelle tethering, and extracellular endocrine signaling, which converge on core hallmarks of aging and explain how peptide loss accelerates tissue decline while restoration or exogenous administration often improves function and extends healthspan in model systems.

Despite promise, discovery and translation face major hurdles. Detection of low‑abundance, low‑MW peptides remains difficult, complicating discrimination of functional translation from noise. Functional assignment often lacks rigorous evidence, and mapping transient, low‑affinity peptide–protein interactions is technically challenging. Context dependence (cell type, metabolic state, sex, disease) further complicates interpretation. Translational barriers include peptide instability, poor tissue delivery, immunogenicity, and safety concerns. Addressing these issues requires standardized functional criteria, improved peptidomics and ribosome profiling, structural and interactome studies, and long‑term aging‑relevant endpoints in preclinical models.

Short peptides present several therapeutic modalities, inclduing direct peptide drugs (stabilized or conjugated analogs), gene‑ or mRNA‑based expression (AAV, mRNA‑LNP), small‑molecule mimetics of peptide actions, and engineered multifunctional micropeptides or delivery platforms for tissue targeting. They also hold biomarker potential for biological aging. To advance translation, expanded discovery with combined Ribo‑seq and tailored peptidomics and public sORF atlases would provide a foundation for short peptides application in the future. Notably, structure identification and design and robust delivery and stabilization strategies development can be the key for its broader impact.

By demonstrating that minimal sequences can exert highly specific control over central aging mechanisms, short peptides bridge molecular simplicity and systemic resilience. With continued methodological innovation and mechanistic dissection, they offer a novel class of geroprotective agents that could complement existing approaches to delay senescence and treat age‑related disease.

Acknowledgements

This work is supported by Natural Science Foundation of China project (42207342), Henan Province Natural Science Foundation (252300420641), Henan Provincial Medical Science and Technology Research Joint Venture Project (SBGJ202403038), and Henan Provincial Science and Technology Research Project (242102311189).

Author contributions

Conceived and designed the work: X.S. and X.X.; literature search: Y.L., X.Z., and P.F.; wrote the paper: Y.L., X.S., C.Q., and X.X.

Data availability

“No datasets were generated or analysed during the current study.”

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Ya Li, Xiangzhan Zhu, Pengya Feng.

Contributor Information

Xia Xue, Email: xue-xiasophia@hotmail.com.

Xiangdong Sun, Email: sunxd0593@126.com.

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