Men are capable of becoming fathers after puberty to the end of their lives. While sperm are produced from sexual maturity to death, the aging process has an impact on reproductive capacity. As a man ages his fertility decreases through a number of mechanisms such as cellular dysfunction, alteration in reproductive endocrine function as well as increased susceptibility to disease. As he grows older these mechanisms lead to subfertility, decreased testosterone levels, and decreased testicular size and weight. The offspring of older men are at increased risk of congenital and other disorders due to decreased DNA stability, DNA mutations and changes in DNA methylation. During the aging process telomere length is shortened.
A recent paper by Jingtao Guo of the Beijing Institute for Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Science and Bradley Cairns from the Howard Hughes Institute, Department of Oncological Sciences and Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine, University of Utah and their colleagues published in Nature Aging in April 2025. They studied 214,369 single-cell transcriptomes in testicular cells from 35 donors aged 21 to 69 years of age (3 men in their 20’s, 4 in their 30’s, 10 in their 40’s, 3 in their 50’s and 10 in their 60’s). The donors were from Utah, Southeast Idaho, Western Wyoming and Elko, Nevada. They consented to donate testicular tissue upon their death. The paper describes the meticulous handling of the tissue and its analysis leading to a single-cell transcriptomic atlas of the testis throughout the lifespan. Using well documented bioinformatics platforms, the researchers used machine learning to discover new findings on testicular aging. The paper is well worth careful and detailed reading of both its methodology and its important findings. All testicular single cells were carefully identified using known genetic markers of germ cells involved spermatogenesis as well as in testicular somatic cells. Differential gene expression was validated experimentally. The researchers have succeeded in producing a useful dataset of testicular single-cell transcriptomes that provides insights into how testicular aging unfolds. They discovered that testicular aging encompasses both gradual and acute genetic and cellular changes. These observed modifications include a continuous increased immune response in the testicular cells in male reproductive aging. There were abrupt key age-related alterations that occurred suddenly at age 30 that included increased basement membrane thickness in testicular peritubular cells as demonstrated by changes in expression of genes in extracellular matrix and collagen I metabolic pathways. The peritubular cells in samples from men in their thirties exhibited the most significant changes in gene expression and dynamic pathways across all the ages of men studied. During the 50’s changes were noted in the Sertoli and Leydig cells. The Leydig cells demonstrated significant modifications in the ability to synthesize and metabolize testosterone. These modifications in Leydig cell function regulated the testosterone microenvironment and spermatogenesis. At fifty the Sertoli cells showed changes in nutrient -related genes such as Insulin growth factor 1 receptor, which regulated cellular processes of growth, proliferation and survival. Thus, there are two waves of molecular and cellular changes the occur in human testis aging. During the first wave testicular peritubular cells have a lower threshold to “switch” to extracellular matrix related genes. The other somatic cells show minimal transcriptomic changes at this age. The second wave occurs later in the 50’s. In this wave the age associated transcriptomic characteristics are amplified and allow for inflammation, decreased testosterone and increased extracellular matrix which are a hallmark of aging in the male testes.
The changes observed in the germ cells during the aging process are interesting. Spermatogonial stem cell counts decreased in the 50’s. Although decreased the spermatogonial stem cells showed minimal transcription changes across all ages. Interestingly differentiating spermatogonia increased during aging. These are the cells that rapidly proliferate and differentiate prior to entering meiosis. These cells are highest during the 30’s and 40’s and maintain continuous spermatogenesis as men age. Donors in the 60’s had a notable increase in differentiating spermatogonia as well. This increase would ensure sperm production in older men. Spermatids however, exhibited dynamic alterations in gene expression during the aging process. Spermatid counts in older men did not change, but the ability for normal flagellation and metamorphosis in round and elongated spermatids declined resulting in abnormal spermatids.
Finally, the researchers studied the relationship of body mass index effect on testicular aging. They found that body mass index-related changes resemble age-related changes in somatic cells. They suggest that an elevated body-mass index accelerates testicular aging, supporting the hypothesis that environmental factors influence sperm production. The paper includes numerous and helpful illustrations and supplemental data and provides information for accessing the database online. This testicular aging atlas will be a very useful tool for future research endeavors.
Reference:
Cui L, Nie X, Guo Y, Ren P, Guo Y, Wang X, Li R, Hotaling JM, Cairns BR, Guo J. Single-cell transcriptomic atlas of the human testis across the reproductive lifespan. Nat Aging. 2025 Apr;5(4):658-674. doi: 10.1038/s43587-025-00824-2. Epub 2025 Mar 3. PMID: 40033047; PMCID: PMC12003174.