We conducted a comprehensive systematic review of studies focusing on aging in TGD individuals. The findings indicate a significant risk of cardiovascular disease, along with occurrences of depression and disability within the TGD population. Additionally, there is a noticeable reluctance to adhere to key recommended screening programs. Nevertheless, there remains a notable gap in available data concerning the aging process in TGD individuals, leaving numerous questions unanswered.

Undoubtedly, the aging trajectory of the TGD population is shaped by social determinants of health at both individual and community levels. Importantly, there persists a deficiency in social support and the provision of inclusive, dignified care for TGD individuals [20]. Specifically, the prevalence of homophobia, transphobia, rejection, and discrimination experienced by TGD individuals, collectively termed "minority stress," disproportionately impacts their overall health and carries significant clinical implications [20]. For instance, individuals enduring minority stress face an elevated risk of developing depression and other psychiatric conditions [21]. Furthermore, apprehension about potential judgment from healthcare professionals leads to a reluctance among TGD individuals to seek medical attention, whether for primary care or screening procedures [21]. Lastly, while limited data are currently available, minority stress could potentially contribute to the observed higher mortality rates in the TGD population [22].

The subsequent sections of this review expound upon the primary areas addressed and the associated evidence.

TGD individuals appear to face a heightened risk of cognitive impairment and Alzheimer's disease (AD) compared to their cisgender counterparts [9]. Elevated levels of stress hormones, linked to accelerated brain aging and cognitive decline, alongside multiple stressors, may contribute to negative self-perceptions and maladaptive psychological phenomena, triggering physical and mental health disorders [23]. Furthermore, increased cortisol levels, dysregulation of the hypothalamic–pituitary–adrenal axis, and the cumulative physiological toll of prolonged stress, known as "allostatic load," can lead to functional and structural damage throughout the body [23]. Considering these factors, it is plausible that minority stress plays a significant role in the onset of dementia [23]. Moreover, there are notable disparities in the prevalence of various modifiable risk factors for both dementia and AD among TGD individuals. Key data highlight significantly higher rates of depression and smoking in TGD individuals (both t-AFAB and t-AMAB), along with higher rates of diabetes and obesity [24]. Previous studies have indicated a considerably higher prevalence of depression in TGD women compared to the cisgender population, with a lifetime prevalence of 62% versus 16.6% for the general US population [25]. This is concerning given that depression is a well-established risk factor for AD in later life [24]. Additionally, some studies have reported that TGD individuals are nearly twice as likely to experience mild cognitive impairment (MCI) and more than twice as likely to report related functional limitations, such as reduced ability to work, volunteer, or socialize, compared with women or men [26].

Cognitive aging in the TGD population has received limited attention thus far, necessitating further studies to gain a better understanding of potential mechanisms, including the specific impact of minority stress on cognition in LGBT individuals.

While the constituents of feminizing therapy have evolved over time, emerging evidence suggests that TGD individuals may face a heightened cardiovascular risk compared to their cisgender counterparts. Regrettably, studies focusing on individuals aged 50 and above are notably scarce. Proposed pathophysiological mechanisms include increased body fat and insulin resistance, alongside compromised endothelial function in t-AMAB individuals [27]. Additionally, platelet activation leading to elevated coagulation and inflammation markers has been implicated [27]. T-AFAB individuals appear to exhibit elevated lipids, including total cholesterol, triglycerides, and low-density lipoprotein, as well as increased levels of high-sensitivity C-reactive protein [27]. Conversely, testosterone therapy may elevate hematocrit, potentially impacting vascular health. While the incidence of vascular complications due to secondary erythrocytosis from masculinizing GAHT is reassuringly low, further research is imperative to comprehensively comprehend the clinical implications of erythrocytosis in this context [28]. Lastly, the escalation of cardiovascular risk factors in transgender individuals, encompassing smoking habits, inadequate nutrition, and sedentary lifestyles, assumes a pivotal role; minority stress associated with gender dysphoria is posited as a major catalyst for these unhealthy lifestyle habits.

In the course of the gender affirmation process, TGD individuals are subjected to prolonged and high-dose administration of exogenous hormones [29]. Consequently, the potential carcinogenic effects of GAHT in aging TGD individuals have become a subject of notable interest and concern. However, comprehensive investigations into the impact of long-term masculinizing and feminizing GAHT on cancer risk in older TGD individuals remain limited, primarily due to the relatively youthful age of participants in existing studies. The absence of well-defined guidelines further compounds the challenge in assessing cancer risk among TGD individuals undergoing masculinization or feminization therapy [28]. Studies conducted in younger TGD individuals indicate several factors implicated in neoplastic risk, including a higher prevalence of sexually transmitted infections, increased exposure to recognized risk factors such as smoking and alcohol use, and insufficient access to adequate screening [30, 31]. Reported cases of malignancies linked to hormones in transgender women undergoing gender affirmation treatments encompass breast and prostate carcinomas, prolactinomas, and meningiomas [32, 33]. For transgender men, clinical reports describe tumors in the breast, ovaries, cervix, vagina, and endometrium [29]. Despite the reported overall incidence of 0.04% for prostate cancer in t-AFAB individuals, the actual incidence of prostate and breast cancer in the TGD population remains uncertain due to limitations in existing cohort studies. Some studies even suggest that the incidence may be lower or at least comparable to that among cisgender individuals [29, 34,35,36]. However, with advancing age, the risk increases, and the influence of environmental factors and lifestyle should not be underestimated.

Surveys conducted in Europe between 2013 and 2014 highlight that 46–80% of TGD individuals are sexually active, with a majority being heterosexual, favoring anal sex, and engaging in multiple sexual partnerships [28]. Additionally, sexually active t-AMAB individuals display a lower inclination to use condoms during receptive anal sex with their primary partners. Financial challenges sometimes propel individuals towards engaging in high-risk sexual behaviors, including having multiple sex partners, unprotected sex, and involvement in commercial sex work [28]. Consequently, TGD individuals face a substantial risk of HIV infection and other sexually transmitted infections, such as human papillomavirus (HPV), potentially leading to a higher risk of cervical, anal, and oropharyngeal cancers. However, the actual prevalence of cervical high-risk HPV infection in the overall transmasculine adult population remains unknown [28].

A notable deficiency in current research pertains to the scarcity of data on bone health in TGD individuals. Studies focusing on young TGD adults reveal diminished bone mineral density (BMD) values in t-AMAB individuals undergoing feminizing therapy even before the initiation of GAHT [37, 38]. In comparison to their cisgender counterparts, reduced BMD is associated with higher cortical porosity, lower trabecular density and number, and increased trabecular separation [38, 39].  The underlying reasons remain unclear, but lifestyle factors may exert a significant influence, with low engagement in outdoor physical activities, suboptimal nutritional habits, and particularly smoking possibly compromising the attainment of peak bone mass [37, 38]. Studies conducted during GAHT have suggested that, after approximately 12–24 months, masculinizing hormone therapy in t-AFAB individuals is not significantly linked to changes in Bone Mineral Density (BMD). Conversely, feminizing hormone therapy in t-AMAB individuals has been associated with increased BMD at the lumbar spine [40, 41]. Unfortunately, limited data are available on the risk of fractures in TGD patients. Wiepjes et al. examined fractures, obtained from emergency department data, in TGD patients in comparison to the cisgender population [41]. Fracture risk was higher in older t-AMAB individuals only when compared to age-matched cisgender men (OR: 1.90, 95% CI: 1.32–2.74) but was lower in t-AFAB individuals compared to cisgender men (OR: 0.57, 95% CI: 0.35–0.94) [41]. Additionally, AMAB individuals were reported to have lower grip strength and reduced levels of total and appendicular lean mass [37]. The long-term implications of these findings, such as potential complications in muscle performance across various body systems or areas, remain unknown.

Recently, a new taxonomic entity known as "couplepause" has been emerging. This term refers to the consequences of hormonal and age-related changes that can lead to an alteration in sexual functionality within a couple, thereby concretizing the combined impact of menopause and andropause on the sexual health of older couples, resulting in simultaneous age-related changes for both members of the couple [42]. This underscores the importance of adopting an approach that is no longer centered solely on the individual but rather directed towards the couple, to comprehensively address the sexual health needs of elderly couples [42, 43]. Challenges associated with aging in couple dynamics primarily involve hormonal decline, coupled with relational issues, changes in social strength, and concurrent illnesses [43]. Recently, a group of experts has proposed enhancing the education of couples, utilizing specific educational materials to facilitate understanding of age-related changes. This actively involves both men and women in collaboratively managing symptoms and self-care. Furthermore, the working group emphasizes the importance of providing comprehensive training for healthcare professionals so that they can acquire the necessary skills to address sexual health during consultations [43]. Despite the term "couplepause" having been predominantly used so far to describe the impacts of menopause and andropause on heterosexual couples, attention should also be directed towards the sexual health of TGD individuals. Aspects such as gender transition, hormone therapies, and related surgeries may be significant elements influencing couple sexual health, especially with aging. The current lack of literature on this topic highlights the need to delve into the theme of "couplepause" in these individuals as well.

One primary limitation of the existing research is its predominant focus on higher-income populations, thereby lacking representativeness for the global population. Few studies have been conducted in low- and middle-income countries (LMIC), potentially restricting the generalizability of the findings. Moreover, certain studies contain possible confounders that might influence the ultimate results. We acknowledge that certain strategies, such as the inclusion of studies only in the English language, could have enhanced the specificity of our literary search. Furthermore, we extended our research to include individuals aged 45 or older, which does not align with the WHO guidelines for the elderly category. However, this decision allowed us to select a greater number of articles in light of the limited literature available on older individuals. Nevertheless, we did not impose restrictions on the publication timeframe of studies. Additionally, we conducted a thorough analysis of citations from key articles to identify further related research, and we scrutinized the bibliographies of relevant articles and literature reviews to uncover additional pertinent sources. We believe these considerations contribute valuable strengths to our work. Furthermore, our review's strength lies in its specific emphasis on transgender individuals aged 45 and above. Given the scarcity of evidence regarding the life expectancy of transgender individuals, our study stands out as one of the few investigations concentrating on older populations experiencing gender dysphoria.