Advanced Paternal Age and Sperm Proteome Dynamics: A Possible Explanation for Age-Associated Male Fertility Decline
Male fertility is strongly influenced by environmental exposures, lifestyle, and advancing age. While advanced paternal age (APA) has been linked with a progressive decline in male fertility, poor reproductive outcomes, and decreased offspring health, the molecular mechanisms underlying these altera...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-05-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/11/813 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849330851611934720 |
|---|---|
| author | Joana Santiago Joana V. Silva Manuel A. S. Santos Margarida Fardilha |
| author_facet | Joana Santiago Joana V. Silva Manuel A. S. Santos Margarida Fardilha |
| author_sort | Joana Santiago |
| collection | DOAJ |
| description | Male fertility is strongly influenced by environmental exposures, lifestyle, and advancing age. While advanced paternal age (APA) has been linked with a progressive decline in male fertility, poor reproductive outcomes, and decreased offspring health, the molecular mechanisms underlying these alterations remain unclear. In this work, we investigated the impact of men’s age on human sperm protein expression and phosphorylation to identify molecular alterations possibly responsible for the age-associated decline in male fertility. Semen samples from volunteers attending fertility consultations at the Hospital of Aveiro were collected, analyzed according to WHO’s guidelines, and processed by the density gradient technique. The proteome and phosphoproteome of 19 normozoospermic human sperm samples divided into four age groups were evaluated by mass spectrometry: ≤30 years old; 31–35 years old; 36–40 years old; and >40 years old. Proteomic analysis revealed 46 differentially expressed proteins (DEPs) between groups, some of them associated with infertility-related phenotypes. Gene ontology (GO) analysis, performed using the DAVID database, revealed that DEPs in older men were enriched in pathways related to stress response, metabolism, and embryo implantation. Additionally, 94 differentially phosphorylated sites corresponding to 76 differentially expressed phosphorylated proteins between the groups were identified, related to key reproductive processes such as sperm motility, spermatogenesis, and sperm binding to zona pellucida, and involved in metabolic and stress response pathways, like HSF1 activation. The set of proteins and phosphorylated residues altered in the sperm fraction usually used in assisted reproductive technology (ART) highlights the need to consider the age of the male partner during fertility assessment and treatment planning. These markers can also be used to explain cases of idiopathic infertility, failure in ART, or repeated abortion associated with APA, overcoming the subjectivity of the conventional semen analysis. |
| format | Article |
| id | doaj-art-cdf06a64de7b41e798537580907a14a3 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-cdf06a64de7b41e798537580907a14a32025-08-20T03:46:48ZengMDPI AGCells2073-44092025-05-01141181310.3390/cells14110813Advanced Paternal Age and Sperm Proteome Dynamics: A Possible Explanation for Age-Associated Male Fertility DeclineJoana Santiago0Joana V. Silva1Manuel A. S. Santos2Margarida Fardilha3Department of Medical Sciences, Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, PortugalDepartment of Medical Sciences, Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, PortugalMultidisciplinary Institute of Ageing, MIA-Portugal, University of Coimbra, 3000-370 Coimbra, PortugalDepartment of Medical Sciences, Institute of Biomedicine, University of Aveiro, 3810-193 Aveiro, PortugalMale fertility is strongly influenced by environmental exposures, lifestyle, and advancing age. While advanced paternal age (APA) has been linked with a progressive decline in male fertility, poor reproductive outcomes, and decreased offspring health, the molecular mechanisms underlying these alterations remain unclear. In this work, we investigated the impact of men’s age on human sperm protein expression and phosphorylation to identify molecular alterations possibly responsible for the age-associated decline in male fertility. Semen samples from volunteers attending fertility consultations at the Hospital of Aveiro were collected, analyzed according to WHO’s guidelines, and processed by the density gradient technique. The proteome and phosphoproteome of 19 normozoospermic human sperm samples divided into four age groups were evaluated by mass spectrometry: ≤30 years old; 31–35 years old; 36–40 years old; and >40 years old. Proteomic analysis revealed 46 differentially expressed proteins (DEPs) between groups, some of them associated with infertility-related phenotypes. Gene ontology (GO) analysis, performed using the DAVID database, revealed that DEPs in older men were enriched in pathways related to stress response, metabolism, and embryo implantation. Additionally, 94 differentially phosphorylated sites corresponding to 76 differentially expressed phosphorylated proteins between the groups were identified, related to key reproductive processes such as sperm motility, spermatogenesis, and sperm binding to zona pellucida, and involved in metabolic and stress response pathways, like HSF1 activation. The set of proteins and phosphorylated residues altered in the sperm fraction usually used in assisted reproductive technology (ART) highlights the need to consider the age of the male partner during fertility assessment and treatment planning. These markers can also be used to explain cases of idiopathic infertility, failure in ART, or repeated abortion associated with APA, overcoming the subjectivity of the conventional semen analysis.https://www.mdpi.com/2073-4409/14/11/813advanced paternal agemale infertilityproteinphosphorylationspermatozoa |
| spellingShingle | Joana Santiago Joana V. Silva Manuel A. S. Santos Margarida Fardilha Advanced Paternal Age and Sperm Proteome Dynamics: A Possible Explanation for Age-Associated Male Fertility Decline Cells advanced paternal age male infertility protein phosphorylation spermatozoa |
| title | Advanced Paternal Age and Sperm Proteome Dynamics: A Possible Explanation for Age-Associated Male Fertility Decline |
| title_full | Advanced Paternal Age and Sperm Proteome Dynamics: A Possible Explanation for Age-Associated Male Fertility Decline |
| title_fullStr | Advanced Paternal Age and Sperm Proteome Dynamics: A Possible Explanation for Age-Associated Male Fertility Decline |
| title_full_unstemmed | Advanced Paternal Age and Sperm Proteome Dynamics: A Possible Explanation for Age-Associated Male Fertility Decline |
| title_short | Advanced Paternal Age and Sperm Proteome Dynamics: A Possible Explanation for Age-Associated Male Fertility Decline |
| title_sort | advanced paternal age and sperm proteome dynamics a possible explanation for age associated male fertility decline |
| topic | advanced paternal age male infertility protein phosphorylation spermatozoa |
| url | https://www.mdpi.com/2073-4409/14/11/813 |
| work_keys_str_mv | AT joanasantiago advancedpaternalageandspermproteomedynamicsapossibleexplanationforageassociatedmalefertilitydecline AT joanavsilva advancedpaternalageandspermproteomedynamicsapossibleexplanationforageassociatedmalefertilitydecline AT manuelassantos advancedpaternalageandspermproteomedynamicsapossibleexplanationforageassociatedmalefertilitydecline AT margaridafardilha advancedpaternalageandspermproteomedynamicsapossibleexplanationforageassociatedmalefertilitydecline |