Age-related arterial telomere uncapping and senescence is greater in women compared with men

Walker, Ashley E.; Morgan, R. Garrett; Ives, Stephen J.; Cawthon, Richard M.; Andtbacka, Robert H.I.; Noyes, Dirk; Lesniewski, Lisa A.; Richardson, Russell S.; Donato, Anthony J.

doi:10.1016/j.exger.2015.11.009

Cited by 13 publications

(8 citation statements)

References 42 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…From the existing literature, female sex is associated with reduced capacity for DNA repair in different organs and cell types (Broestl et al, 2022; Kfoury et al, 2018; Malorni et al, 2008; Rall‐Scharpf et al, 2021; Sun et al, 2014; Trzeciak et al, 2008), with one exception to this assumption found by Yousefzadeh et al (2020). Walker et al found that age (>55 y/o) has a greater effect on activating DNA damage response and senescence in aged women compared with aged men (Walker et al, 2016). We found that 150 μM FC significantly increased DNA damage in aged female mouse‐derived CEC, compared with female CEC treated either with 50 μM FC or a vehicle.…”

Section: Discussionmentioning

confidence: 99%

Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex‐dependent manner

Noh,

Blasco‐Conesa,

Rahman

et al. 2023

Aging Cell

View full text Add to dashboard Cite

Iron imbalance in the brain negatively affects brain function. With aging, iron levels increase in the brain and contribute to brain damage and neurological disorders. Changes in the cerebral vasculature with aging may enhance iron entry into the brain parenchyma, leading to iron overload and its deleterious consequences. Endothelial senescence has emerged as an important contributor to age‐related changes in the cerebral vasculature. Evidence indicates that iron overload may induce senescence in cultured cell lines. Importantly, cells derived from female human and mice generally show enhanced senescence‐associated phenotype, compared with males. Thus, we hypothesize that cerebral endothelial cells (CEC) derived from aged female mice are more susceptible to iron‐induced senescence, compared with CEC from aged males. We found that aged female mice, but not males, showed cognitive deficits when chronically treated with ferric citrate (FC), and their brains and the brain vasculature showed senescence‐associated phenotype. We also found that primary culture of CEC derived from aged female mice, but not male‐derived CEC, exhibited senescence‐associated phenotype when treated with FC. We identified that the transmembrane receptor Robo4 was downregulated in the brain vasculature and in cultured primary CEC derived from aged female mice, compared with those from male mice. We discovered that Robo4 downregulation contributed to enhanced vulnerability to FC‐induced senescence. Thus, our study identifies Robo4 downregulation as a driver of senescence induced by iron overload in primary culture of CEC and a potential risk factor of brain vasculature impairment and brain dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex‐dependent manner

Noh,

Blasco‐Conesa,

Rahman

et al. 2023

Aging Cell

View full text Add to dashboard Cite

show abstract

“…Women have a greater increase in arterial telomere uncapping with age compared with men (32), indicating a possible interaction of aging and menopause. Fasting blood glucose positively correlates with vascular telomere uncapping in women but not in men, whereas systolic blood pressure and pulse pressure positively correlate with vascular telomere uncapping in men but not in women (32). Thus, the rate and causes of vascular telomere uncapping may differ between the sexes.…”

Section: Vascular Telomere Uncapping With Agingmentioning

confidence: 94%

Telomere uncapping and vascular aging

Morgan

Donato

Walker

2018

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

Although most telomere biology research continues to focus on telomere shortening, there is increasing evidence that telomere deprotection, or "uncapping," is more biologically and possibly clinically important. Telomeres form t-loops to prevent the chromosome ends from appearing as a double-stranded DNA break and initiating a DNA damage response. Breakdown of the t-loop structure, referred to as uncapping, can lead to cellular senescence, increased oxidative stress, and inflammation in tissues. In this review, we describe how telomere uncapping potentially leads to age-related vascular dysfunction and increased cellular senescence, oxidative stress, and inflammation. Importantly, we present evidence to argue that telomere uncapping is more biologically relevant than telomere shortening and a better marker of vascular aging and target for antiaging interventions.

show abstract

“…However, our knowledge about sex differences in endothelial cellular senescence is very limited. An age-related increase in arterial telomere uncapping and senescence is greater in women than men ( Walker et al, 2016 ), indicating a sex difference in vascular senescence. Future studies should reveal the key players, mechanisms, and signaling pathways about it in both preclinical animal models and human subjects including postmenopausal females and age-matched males.…”

Section: Cellular Senescence Of Endothelial Cellsmentioning

confidence: 99%

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

Sun

Feinberg

2021

Front. Physiol.

View full text Add to dashboard Cite

Cellular senescence is a stable form of cell cycle arrest in response to various stressors. While it serves as an endogenous pro-resolving mechanism, detrimental effects ensue when it is dysregulated. In this review, we introduce recent advances for cellular senescence and inflammaging, the underlying mechanisms for the reduction of nicotinamide adenine dinucleotide in tissues during aging, new knowledge learned from p16 reporter mice, and the development of machine learning algorithms in cellular senescence. We focus on pathobiological insights underlying cellular senescence of the vascular endothelium, a critical interface between blood and all tissues. Common causes and hallmarks of endothelial senescence are highlighted as well as recent advances in endothelial senescence. The regulation of cellular senescence involves multiple mechanistic layers involving chromatin, DNA, RNA, and protein levels. New targets are discussed including the roles of long noncoding RNAs in regulating endothelial cellular senescence. Emerging small molecules are highlighted that have anti-aging or anti-senescence effects in age-related diseases and impact homeostatic control of the vascular endothelium. Lastly, challenges and future directions are discussed including heterogeneity of endothelial cells and endothelial senescence, senescent markers and detection of senescent endothelial cells, evolutionary differences for immune surveillance in mice and humans, and long noncoding RNAs as therapeutic targets in attenuating cellular senescence. Accumulating studies indicate that cellular senescence is reversible. A better understanding of endothelial cellular senescence through lifestyle and pharmacological interventions holds promise to foster a new frontier in the management of cardiovascular disease risk.

show abstract

Age-related arterial telomere uncapping and senescence is greater in women compared with men

Cited by 13 publications

References 42 publications

Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex‐dependent manner

Iron overload induces cerebral endothelial senescence in aged mice and in primary culture in a sex‐dependent manner

Telomere uncapping and vascular aging

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

Contact Info

Product

Resources

About