Increased Expression of Retrotransposons in Human Blood Correlates with Biological Aging

מושגי ליבה

The expression of most retrotransposon classes, except short interspersed nuclear elements (SINEs), positively correlates with age-associated gene signature scores, suggesting a role for retrotransposons in biological aging. In contrast, SINE expression is linked to upregulated DNA repair pathways.

תקציר

The study systematically analyzed the relationship between retrotransposon (RTE) expression and aging using published transcriptomic and methylomic datasets of human blood. Key findings:

Chronological age is not linked with RTE expression, but most RTE classes and families (except SINEs) correlate with age-associated gene signature scores.

SINE expression is associated with upregulated DNA repair pathways, while LINE and LTR expressions are linked to increased inflammatory response.

DNA hypomethylation with aging was observed across RTE classes and associated with increased RTE expression, except for SINEs.

Single-cell transcriptomic analysis suggests a role for plasma cells in aging mediated by RTEs.

Supercentenarians show decreased RTE expression in most immune cell types compared to normal-aged individuals, despite increased age-associated signatures in natural killer and T cells.

The study provides insights into the complex relationship between RTE expression, DNA methylation, and biological aging, highlighting the distinct roles of SINE versus LINE and LTR retrotransposons. Further investigations are needed to elucidate the mechanisms by which RTEs may contribute to the aging process and age-related diseases.

סטטיסטיקה

Chronological age ranges from 15 to 83 years across the analyzed cohorts.
The mean chronological ages are 70.2 (MESA), 60.1 (GARP), and 42.5 (GTP).

ציטוטים

"Strikingly, we found that the expression of SINEs is linked to upregulated DNA repair pathways in multiple cohorts."
"DNA hypomethylation with aging was observed across RTE classes and associated with increased RTEs expression in most RTE classes and families except SINEs."
"Altogether, our multi-omics analysis of large human cohorts highlights the role of RTEs in biological aging and suggests possible mechanisms and cell populations for future investigations."

תובנות מפתח מזוקקות מ:

Expression of Most Retrotransposons in Human Blood Correlates with Biological Aging

by Tsai,Y.-T., ... ב- www.biorxiv.org 02-12-2024

https://www.biorxiv.org/content/10.1101/2024.02.09.579582v2

שאלות מעמיקות

What are the potential mechanisms by which SINE expression may contribute to DNA repair pathways during aging?

Short Interspersed Nuclear Elements (SINEs) are a type of retrotransposon that can impact DNA repair pathways during aging through several potential mechanisms:

Genome Instability: SINEs, particularly Alu elements, can insert themselves into the genome, leading to DNA damage and genome instability. This DNA damage can trigger DNA repair pathways to maintain genomic integrity.

Activation of Repair Machinery: The presence of SINEs in the genome can activate DNA repair machinery as a response to the recognition of foreign DNA elements. This activation can lead to an upregulation of DNA repair pathways to address the damage caused by SINE insertions.

Epigenetic Changes: SINEs have been associated with changes in DNA methylation patterns, which can influence the expression of genes involved in DNA repair. Hypomethylation of SINEs, commonly observed during aging, can lead to altered gene expression profiles, including those related to DNA repair.

Inflammatory Response: SINEs can also trigger an inflammatory response, which is closely linked to DNA repair processes. Inflammation can induce DNA damage, leading to the activation of repair mechanisms to mitigate the effects of inflammation on genomic stability.

Overall, the presence and activity of SINEs, particularly Alu elements, can impact DNA repair pathways during aging by inducing DNA damage, activating repair machinery, influencing epigenetic changes, and triggering inflammatory responses.

How do the age-associated inflammatory and senescence signatures in natural killer and T cells of supercentenarians arise without increased RTE expression?

The age-associated inflammatory and senescence signatures observed in natural killer (NK) and T cells of supercentenarians can arise without increased Retrotransposon Elements (RTE) expression through several mechanisms:

Epigenetic Regulation: While RTE expression is commonly associated with aging and age-related diseases, the inflammatory and senescence signatures in NK and T cells of supercentenarians may be regulated by epigenetic mechanisms other than RTE expression. Epigenetic modifications, such as changes in DNA methylation and histone modifications, can influence gene expression patterns related to inflammation and senescence.

Cellular Senescence: The inflammatory and senescence signatures in NK and T cells may be driven by cellular senescence, a state of irreversible cell cycle arrest associated with aging. Cellular senescence can lead to the secretion of pro-inflammatory cytokines and the development of the senescence-associated secretory phenotype (SASP) without a direct correlation with RTE expression.

Immunosenescence: Immunosenescence, the age-related decline in immune function, can contribute to the inflammatory and senescence signatures observed in NK and T cells of supercentenarians. Changes in immune cell function and signaling pathways associated with immunosenescence can lead to the activation of inflammatory and senescence pathways independent of RTE expression.

Alternative Pathways: Other molecular pathways and signaling cascades, such as oxidative stress, mitochondrial dysfunction, and cellular metabolism, can also contribute to the age-associated inflammatory and senescence signatures in NK and T cells without a direct increase in RTE expression.

In summary, the inflammatory and senescence signatures in NK and T cells of supercentenarians can arise through a combination of epigenetic regulation, cellular senescence, immunosenescence, and alternative molecular pathways, even in the absence of increased RTE expression.

Could the differential regulation of RTE classes be exploited as a biomarker or therapeutic target for healthy aging and age-related diseases?

The differential regulation of Retrotransposon Elements (RTE) classes, such as Long Interspersed Nuclear Elements (LINEs), Short Interspersed Nuclear Elements (SINEs), and Long Terminal Repeat (LTR) retrotransposons, could indeed be exploited as a biomarker or therapeutic target for healthy aging and age-related diseases. Here are some ways in which this differential regulation could be utilized:

Biomarker Development: The distinct patterns of RTE expression observed in different cell types and age-related gene signatures could serve as biomarkers for assessing biological aging and age-related diseases. Monitoring the expression levels of specific RTE classes could provide insights into the aging process and the development of age-related pathologies.

Therapeutic Target Identification: Targeting the dysregulated RTE classes, such as LINEs and LTRs associated with inflammation and senescence, could offer therapeutic opportunities for mitigating age-related inflammatory processes and cellular senescence. Modulating the expression or activity of specific RTE classes could potentially alleviate age-related pathologies.

Epigenetic Interventions: Strategies aimed at modulating the epigenetic regulation of RTEs, such as DNA methylation and histone modifications, could be explored as therapeutic interventions for healthy aging. Restoring proper epigenetic control over RTE expression could help maintain genomic stability and reduce the impact of RTE dysregulation on aging processes.

Immunomodulation: Targeting RTE-mediated inflammatory responses through immunomodulatory approaches could be beneficial for managing age-related inflammation and associated diseases. Modulating the immune response triggered by RTE expression could help alleviate inflammation and its detrimental effects on aging.

In conclusion, the differential regulation of RTE classes holds promise as a biomarker for assessing aging and age-related diseases and as a potential therapeutic target for promoting healthy aging and combating age-related pathologies. Further research and clinical studies are needed to explore the full potential of targeting RTE classes in the context of healthy aging and age-related diseases.