Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology.

Miller B, Kim SJ, Cao K, Mehta HH, Thumaty N, Kumagai H, Iida T, McGill C, Pike CJ, Nurmakova K, Levine ZA, Sullivan PM and 5 more

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Yen K, Ertekin-Taner N, Atzmon G, Barzilai N, Cohen P

Aging cell22 Mar 2024Cited by 15 (Europe PMC)

PMID38520065PMCIDPMC11258485DOI10.1111/acel.14153PepBankPUB-38520065

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Summary

The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial-derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4-centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid-beta accumulation compared to the wild-type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid-beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4-linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study6

No result from this study comes from a test of the peptide.

Natural levels measured1

These results measure the body's own peptide. Nobody was given the peptide. They are not evidence about taking it. They are left out of key results, evidence counts and charts.

01HumanEndogenous levelObservational studyOther
In the temporal cortex of APOE4 carriers, humanin expression correlated with genes associated with phagocytosis.
In plain wordsIn the brains of APOE4 carriers, the body's own humanin was linked to genes involved in clearing waste by cells.
Peptide
Humanin
Outcome
Direction not reportedHumanin expression correlation with phagocytosis genes
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Source sentences
Summary
Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis.
This result measures the body's own Humanin. Nobody was given the peptide. It is not evidence about taking it.
Show in the study text Report a problemFND-3852006506

Studies that did not test the peptide alone5

In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Humanin.

02HumanNot a test of Humanin aloneObservational studyOther
The humanin variant P3S was enriched in centenarians who carry the APOE4 allele.
In plain wordsA rare humanin variant called P3S was more common in the very oldest people who carry APOE4.
Peptide
Humanin
Outcome
IncreaseHumanin P3S in centenarians with APOE4
Study
n: not reported in source
Outcome group
Aging markers · Aging and longevity
Source sentences
Summary
Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-3852006501
03AnimalNot a test of Humanin aloneAnimal study (in vivo)Efficacy outcome
In APP/PS1/APOE4 mice, humanin P3S attenuated brain amyloid-beta accumulation more than wild-type humanin.
In plain wordsIn mice with an Alzheimer-type model, humanin variant P3S reduced brain amyloid-beta buildup more than regular humanin.
Peptide
Humanin
Outcome
DecreaseBrain amyloid-beta accumulation
Study
mousen: not reported in source
APP/PS1/APOE4 mouse model of amyloidosis
Comparator
Wild-type humanin
Outcome group
Neuroprotection · Nervous system and cognition
Source sentences
Summary
Utilizing an APOE4-centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid-beta accumulation compared to the wild-type humanin.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-3852006503
04AnimalNot a test of Humanin aloneAnimal study (in vivo)Mechanism
In mice treated with humanin P3S, transcriptomic assessment pointed to enhanced amyloid beta phagocytosis as a potential mechanism.
In plain wordsIn mice treated with humanin variant P3S, gene activity patterns pointed to better clearing of amyloid beta by cells.
Peptide
Humanin
Outcome
IncreaseAmyloid beta phagocytosis (transcriptomic)
Study
mousen: not reported in source
APP/PS1/APOE4 mouse model of amyloidosis
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Source sentences
Summary
Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-3852006504
05LabNot a test of Humanin aloneIn vitro (cells)Efficacy outcome
In vitro studies showed that humanin P3S promoted amyloid-beta clearance.
In plain wordsIn lab tests, humanin variant P3S helped clear amyloid-beta.
Peptide
Humanin
Outcome
IncreaseAmyloid-beta clearance in vitro
Study
n: not reported in source
Outcome group
Neuroprotection · Nervous system and cognition
Source sentences
Summary
Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid-beta clearance.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-3852006505
06Computer modelNot a test of Humanin aloneIn silicoMechanism
In silico analyses with experimental validation showed a strong affinity between humanin P3S and APOE4.
In plain wordsComputer analysis with lab checks showed that the humanin variant P3S binds strongly to APOE4.
Peptide
Humanin
Outcome
Not applicableBinding affinity of humanin P3S to APOE4
Study
n: not reported in source
Outcome group
Receptor activity and mechanism · Nervous system and cognition
Source sentences
Summary
Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4.
In this study, Humanin was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Humanin.
Show in the study text Report a problemFND-3852006502

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
13 Oct 2026, 21:44 UTC
Study results updated
Version 1
13 Oct 2026, 16:31 UTC
First added · source update from Europe PMC

Subjects

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