madman
Super Moderator
Key point being stressed here!
* Age-related ED is a manifestation of systemic vascular pathology
* Key contributors to age-related ED include reduced nitric oxide (NO) bioavailability due to endothelial oxidative stress and inflammation, diminished cavernosal smooth muscle content leading to impaired veno-occlusion, and increased arterial stiffness compounded by metabolic disorders. Chronic inflammation, oxidative stress, hormonal imbalances (particularly testosterone deficiency), and metabolic disruption accelerate these vascular aging processes, making ED an early indicator of systemic vascular pathology.
* In the erection process, the corpus cavernosum muscle and ischiocavernosus muscle (ICM) act synergistically to enable and sustain erection. As the core smooth muscle of the corpus cavernosum, the corpus cavernosum muscle relaxes upon sexual stimulation (e.g., reflexive or psychological), expanding the internal vascular spaces (sinusoids) and reducing vascular resistance to accelerate arterial blood inflow, laying the foundation for penile engorgement (7-9). The ICM is a paired, short, pinnate striated muscle attached to the pelvic ring. It originates from the ischial tuberosity and covers the crus of the penis, ending at the crus itself. The ICM plays a critical auxiliary role in achieving and maintaining penile rigidity (10). During erection, the contraction of the ICM compresses the crura of the penis against the pubic bone, which further elevates intracavernous pressure to suprasystolic levels (11). This compression restricts venous outflow, effectively preventing blood from leaving the corpora cavernosa and thus enhancing penile rigidity.
Figure 1 Molecular mechanisms of vascular age-related erectile dysfunction. This schematic contrasts molecular pathways governing penile erection in young versus aged vascular tissues. In the young state (left), ECs convert L-arginine to NO via eNOS, stimulated by ACh; NO diffuses to SMCs, activating sGC to generate cGMP from GTP, promoting SMC relaxation, vasodilation, and erection, while PDE5 degrades cGMP to terminate signaling. Ca2+ homeostasis and endoplasmic reticulum function support normal tone. In the aged state (right), ROS, inflammation (elevated IL-6, TNF-α, ICAM-1, VCAM-1), testosterone deficiency, and eNOS uncoupling cause endothelial DNA damage and apoptosis, reducing NO bioavailability. Concurrently, SMCs exhibit TGF-β1 overexpression, PGE1 reduction, and disrupted cGMP signaling (cGMP↓), leading to fibrosis, Ca2+ dysregulation, endoplasmic reticulum stress, and failed relaxation, collectively driving erectile dysfunction through vascular inflammation, structural remodeling, and impaired vasodilatory pathways. Ca2+, ACh, acetylcholine; Ca, calcium; cGMP, cyclic guanosine monophosphate; ECs, endothelial cells; eNOS, endothelial NO synthase; GC, guanylate cyclase; GTP, guanosine triphosphate; ICAM-1, intercellular adhesion molecule-1; IL-6, interleukin-6; NO, nitric oxide; nNOS, neuronal nitric oxide synthase; PDE5, phosphodiesterase-5; PGE1, prostaglandin E1; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; SMCs, smooth muscle cells; TGF-β1, transforming growth factor beta 1; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1.
Background and Objective
Age-related erectile dysfunction (ED) is a significant health concern linked to vascular aging, characterized by endothelial dysfunction and vascular smooth muscle alterations. This study aimed to explores the pathophysiological mechanisms of age-related ED in elderly men, providing new directions for diagnosis and the development of novel targeted therapies.
Methods
This review focused on literature from 2000 to 2025 concerning vascular aging and ED. We searched PubMed, Web of Science, and Embase using keywords like “erectile dysfunction”, “aging”, “vascular endothelium”, and “vascular smooth muscle”. The selection process prioritized high-quality clinical and innovative preclinical studies in humans or animal models that explored pathophysiology or novel treatments. Exclusion criteria included duplicates, non-peer-reviewed articles, and off-topic studies.
Key Content and Findings
Key contributors to age-related ED include reduced nitric oxide (NO) bioavailability due to endothelial oxidative stress and inflammation, diminished cavernosal smooth muscle content leading to impaired veno-occlusion, and increased arterial stiffness compounded by metabolic disorders. Chronic inflammation, oxidative stress, hormonal imbalances (particularly testosterone deficiency), and metabolic disruption accelerate these vascular aging processes, making ED an early indicator of systemic vascular pathology. Current treatment strategies mainly include phosphodiesterase-5 inhibitors (PDE5i) and testosterone, both of which are suitable for immediate symptom relief in most ED, although there are serious limitations. Emerging interventions are currently experimental and their evidence is mainly derived from preclinical studies. These include interventions to preserve endothelial NO synthase (eNOS) function, stem cell regenerative therapies targeting tissue repair, nanotechnology to enhance the efficiency of drug delivery, and modulation of mitochondrial integrity and inflammation.
Conclusions
Age-related ED is a manifestation of systemic vascular pathology. A deeper understanding of its mechanisms underscores its role as an “early warning signal” for overall vascular health. While current treatments like PDE5i and testosterone offer symptomatic relief, they have limitations. Promising future directions lie in novel targeted therapies, such as enhancing eNOS function, stem-cell therapy, and nanotechnology, which are currently in the experimental stage and require further clinical validation.
* Pathophysiology of vascular aging in ED
* Endothelium and NO/endothelial NO synthase (eNOS)
* Smooth muscle cell (SMC)/veno-occlusion and fibrosis
* Arterial stiffness and inflow limitation
* Systemic inflammation-oxidative stress-hormonal axis
* Hormonal imbalances and metabolic disruption
Therapeutic strategies
- Phosphodiesterase-5 inhibitors (PDE5i)
- Hormonal modulation
- eNOS function preservation
- Stem cell-based regeneration
- Nanotechnology-enabled delivery
Conclusions
Conclusion and future perspectives
Based on the comprehensive review, age-related ED primarily stems from vascular aging, characterized by endothelial dysfunction, reduced NO bioavailability, vascular smooth muscle depletion, and arterial stiffness, exacerbated by chronic inflammation, oxidative stress, and hormonal imbalances. These interrelated mechanisms disrupt penile hemodynamics and neurovascular signaling, positioning ED as an early indicator of systemic vascular pathology. Current therapies like PDE5i and testosterone replacement offer symptomatic relief but exhibit limited efficacy in advanced vascular damage or metabolic comorbidities. Notably, among potential future strategies, targeting endothelial repair and NO bioavailability restoration (e.g., combining PDE5i with antioxidants or hormonal modulators) and stem cell-based cavernosal structure regeneration show considerable promise, as they directly address the core pathophysiological mechanisms of age-related ED. Additionally, nanotechnology-enabled precision delivery could further enhance the bioavailability of these therapeutic interventions to improve outcomes. Exploring biomarkers for early detection and developing personalized approaches focusing on mitochondrial integrity, inflammation resolution, and endothelial repair pathways also hold value for clinical translation. It is important to emphasize that the evidence supporting the aforementioned research models remains primarily at the preclinical stage. Thus, rigorous randomized controlled trials, long-term safety assessments, and comparative effectiveness studies are urgently needed to validate their clinical efficacy and safety before widespread clinical application.
* Age-related ED is a manifestation of systemic vascular pathology
* Key contributors to age-related ED include reduced nitric oxide (NO) bioavailability due to endothelial oxidative stress and inflammation, diminished cavernosal smooth muscle content leading to impaired veno-occlusion, and increased arterial stiffness compounded by metabolic disorders. Chronic inflammation, oxidative stress, hormonal imbalances (particularly testosterone deficiency), and metabolic disruption accelerate these vascular aging processes, making ED an early indicator of systemic vascular pathology.
* In the erection process, the corpus cavernosum muscle and ischiocavernosus muscle (ICM) act synergistically to enable and sustain erection. As the core smooth muscle of the corpus cavernosum, the corpus cavernosum muscle relaxes upon sexual stimulation (e.g., reflexive or psychological), expanding the internal vascular spaces (sinusoids) and reducing vascular resistance to accelerate arterial blood inflow, laying the foundation for penile engorgement (7-9). The ICM is a paired, short, pinnate striated muscle attached to the pelvic ring. It originates from the ischial tuberosity and covers the crus of the penis, ending at the crus itself. The ICM plays a critical auxiliary role in achieving and maintaining penile rigidity (10). During erection, the contraction of the ICM compresses the crura of the penis against the pubic bone, which further elevates intracavernous pressure to suprasystolic levels (11). This compression restricts venous outflow, effectively preventing blood from leaving the corpora cavernosa and thus enhancing penile rigidity.
Figure 1 Molecular mechanisms of vascular age-related erectile dysfunction. This schematic contrasts molecular pathways governing penile erection in young versus aged vascular tissues. In the young state (left), ECs convert L-arginine to NO via eNOS, stimulated by ACh; NO diffuses to SMCs, activating sGC to generate cGMP from GTP, promoting SMC relaxation, vasodilation, and erection, while PDE5 degrades cGMP to terminate signaling. Ca2+ homeostasis and endoplasmic reticulum function support normal tone. In the aged state (right), ROS, inflammation (elevated IL-6, TNF-α, ICAM-1, VCAM-1), testosterone deficiency, and eNOS uncoupling cause endothelial DNA damage and apoptosis, reducing NO bioavailability. Concurrently, SMCs exhibit TGF-β1 overexpression, PGE1 reduction, and disrupted cGMP signaling (cGMP↓), leading to fibrosis, Ca2+ dysregulation, endoplasmic reticulum stress, and failed relaxation, collectively driving erectile dysfunction through vascular inflammation, structural remodeling, and impaired vasodilatory pathways. Ca2+, ACh, acetylcholine; Ca, calcium; cGMP, cyclic guanosine monophosphate; ECs, endothelial cells; eNOS, endothelial NO synthase; GC, guanylate cyclase; GTP, guanosine triphosphate; ICAM-1, intercellular adhesion molecule-1; IL-6, interleukin-6; NO, nitric oxide; nNOS, neuronal nitric oxide synthase; PDE5, phosphodiesterase-5; PGE1, prostaglandin E1; ROS, reactive oxygen species; sGC, soluble guanylate cyclase; SMCs, smooth muscle cells; TGF-β1, transforming growth factor beta 1; TNF-α, tumor necrosis factor-α; VCAM-1, vascular cell adhesion molecule-1.
Background and Objective
Age-related erectile dysfunction (ED) is a significant health concern linked to vascular aging, characterized by endothelial dysfunction and vascular smooth muscle alterations. This study aimed to explores the pathophysiological mechanisms of age-related ED in elderly men, providing new directions for diagnosis and the development of novel targeted therapies.
Methods
This review focused on literature from 2000 to 2025 concerning vascular aging and ED. We searched PubMed, Web of Science, and Embase using keywords like “erectile dysfunction”, “aging”, “vascular endothelium”, and “vascular smooth muscle”. The selection process prioritized high-quality clinical and innovative preclinical studies in humans or animal models that explored pathophysiology or novel treatments. Exclusion criteria included duplicates, non-peer-reviewed articles, and off-topic studies.
Key Content and Findings
Key contributors to age-related ED include reduced nitric oxide (NO) bioavailability due to endothelial oxidative stress and inflammation, diminished cavernosal smooth muscle content leading to impaired veno-occlusion, and increased arterial stiffness compounded by metabolic disorders. Chronic inflammation, oxidative stress, hormonal imbalances (particularly testosterone deficiency), and metabolic disruption accelerate these vascular aging processes, making ED an early indicator of systemic vascular pathology. Current treatment strategies mainly include phosphodiesterase-5 inhibitors (PDE5i) and testosterone, both of which are suitable for immediate symptom relief in most ED, although there are serious limitations. Emerging interventions are currently experimental and their evidence is mainly derived from preclinical studies. These include interventions to preserve endothelial NO synthase (eNOS) function, stem cell regenerative therapies targeting tissue repair, nanotechnology to enhance the efficiency of drug delivery, and modulation of mitochondrial integrity and inflammation.
Conclusions
Age-related ED is a manifestation of systemic vascular pathology. A deeper understanding of its mechanisms underscores its role as an “early warning signal” for overall vascular health. While current treatments like PDE5i and testosterone offer symptomatic relief, they have limitations. Promising future directions lie in novel targeted therapies, such as enhancing eNOS function, stem-cell therapy, and nanotechnology, which are currently in the experimental stage and require further clinical validation.
* Pathophysiology of vascular aging in ED
* Endothelium and NO/endothelial NO synthase (eNOS)
* Smooth muscle cell (SMC)/veno-occlusion and fibrosis
* Arterial stiffness and inflow limitation
* Systemic inflammation-oxidative stress-hormonal axis
* Hormonal imbalances and metabolic disruption
Therapeutic strategies
- Phosphodiesterase-5 inhibitors (PDE5i)
- Hormonal modulation
- eNOS function preservation
- Stem cell-based regeneration
- Nanotechnology-enabled delivery
Conclusions
Conclusion and future perspectives
Based on the comprehensive review, age-related ED primarily stems from vascular aging, characterized by endothelial dysfunction, reduced NO bioavailability, vascular smooth muscle depletion, and arterial stiffness, exacerbated by chronic inflammation, oxidative stress, and hormonal imbalances. These interrelated mechanisms disrupt penile hemodynamics and neurovascular signaling, positioning ED as an early indicator of systemic vascular pathology. Current therapies like PDE5i and testosterone replacement offer symptomatic relief but exhibit limited efficacy in advanced vascular damage or metabolic comorbidities. Notably, among potential future strategies, targeting endothelial repair and NO bioavailability restoration (e.g., combining PDE5i with antioxidants or hormonal modulators) and stem cell-based cavernosal structure regeneration show considerable promise, as they directly address the core pathophysiological mechanisms of age-related ED. Additionally, nanotechnology-enabled precision delivery could further enhance the bioavailability of these therapeutic interventions to improve outcomes. Exploring biomarkers for early detection and developing personalized approaches focusing on mitochondrial integrity, inflammation resolution, and endothelial repair pathways also hold value for clinical translation. It is important to emphasize that the evidence supporting the aforementioned research models remains primarily at the preclinical stage. Thus, rigorous randomized controlled trials, long-term safety assessments, and comparative effectiveness studies are urgently needed to validate their clinical efficacy and safety before widespread clinical application.
