Vascular rejuvenation: a new therapeutic target?

This editorial refers to ‘Telomerase therapy reverses vascular senescence and extends lifespan in progeria mice’, by A. Mojiri et al., https://doi.org/10.1093/eurheartj/ehab547. Triggers of senescence and steps towards targeted rejuvenation therapy. A variety of stressors can activate the cellular senescence programme. Physiologically, cellular senescence is followed by the clearance of senescent cells. However, if the elimination of senescent cells does not occur, the senescent cells accumulate and can lead to diseases associated with ageing. Different therapeutic strategies (in red) can be used to exploit the beneficial aspects of cellular senescence and repress the negative ones, such as the elimination of senescent cells by senolytic therapies or modulation of senescence by cellular reprogramming (i.e. overexpression of hTERT), leading to cell rejuvenation. hTERT, human telomerase reverse transcriptase. Ageing is a major risk factor for cardiovascular disease.1 With the occurrence of cellular ageing, favoured by the exposure to cardiovascular risk factors, comorbidities, and various stressors, such as bouts of ischaemia and/or ischaemia–reperfusion, the function and cross-talk of cardiac stromal cells (CSCs) and vascular and parenchymal cells, including cardiomyocytes, is diminished, hampering their cardioprotective potential.2 Ageing is also an important determinant of metabolic disorders, including obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome.1 Older men and women tend to have worsened glycaemia-related parameters, i.e. fasting and 2-h plasma glucose and HbA1c concentrations, than their younger counterparts. The reason for the increase in the fasting and 2-h plasma glucose with age is likely to be due to an increase in the peripheral insulin resistance (IR), age-related deterioration in β-cell function, physical inactivity, sarcopenia, and obesity. As a result, there have been calls to consider age-dependent hyperglycaemia and HbA1c as the diagnostic cut-off in order to maintain the diagnostic performance of this test.3 On the other hand, diabetic patients are more prone to develop cardiovascular disease, which is associated with worse prognosis as compared with its non-diabetic counterpart. Mechanisms explaining the interplay of ageing, diabetes, and cardiovascular disease are multiple and still largely unclear.4 However, oxidative and hyperosmolar stress, as well as a dysregulated vascular regeneration and the activation of inflammatory pathways triggered by advanced glycation end-products and Toll-like receptors (TORs),4 appear to play a key role. In addition, ageing and metabolic disorders might greatly affect endogenous cardioprotective pathways and the capacity of organs—including the heart—to self-repair after ischaemic injury.5 As ageing is a major risk factor for cardiovascular disease, but also an important determinant of metabolic disorders, including obesity, T2DM, and metabolic syndrome, it acts as common ground between metabolic and cardiovascular disease (so-called cardiometabolic disease). With the onset of ageing and metabolic disorders, the function of vascular and parenchymal cells, including cardiomyocytes, is diminished. These cells are susceptible to age-related changes, including increased rates of apoptosis and senescence, that reduce their ability to contribute to endogenous repair processes. The combination of these age-related deficits may contribute to decreased muscle and vessel regeneration after injury and facilitate the development of atherosclerosis and its sequelae such as ischaemic heart disease (IHD) and heart failure (HF) in aged individuals. These patients might benefit from therapies that would revert cellular senescence of myocardial and vascular cells, an approach referred to as antisenescence or rejuvenating therapy.6 , 7 A complementary approach would be to eradicate senescent cells with targeted approaches, termed ‘senolytic’ therapies (Graphical Abstract). The demonstration that cellular senescence can lead to atherosclerosis comes from the observation that in the atherosclerotic plaques of human coronary arteries, there are a substantial number of vascular senescent cells, which do not occur in the internal mammary artery, notoriously resistant to atherosclerosis.8 These senescent cells in the atherosclerotic plaques exhibit specific functional abnormalities, such as reduced nitric oxide (NO) production, and increased expression of intercellular adhesion molecule-1 (ICAM-1) and proinflammatory cytokines.8 The interplay of oxidative stress and excessive caloric intake as triggers of an insulin/insulin growth factor (IGF)-mediated cell signalling, mTOR activation, formation of mitochondrial reactive oxygen species (ROS), and deregulation of sirtuins9 is among the most accredited molecular mechanisms linking ageing, metabolic disorders, and cardiovascular disease. These all lead to the accumulation of senescent cells in various organs and tissues, including the heart and vessels, determining endothelial dysfunction with progression of atherosclerosis and HF. Therefore, inhibition of vascular and cardiomyocytic senescence can be an effective strategy for the treatment of atherosclerosis and HF. It has also been shown that adipose tissue from obese mice with T2DM exhibits a senescent phenotype, which is associated with an increased expression of p53, p21, and proinflammatory proteins such as tumour necrosis factor (TNF) and interleukin-6 (IL-6), all known as secretory-associated senescence proteins (SASPs). The deletion of p53 in adipose tissue improved insulin sensitivity and glucose tolerance in the murine model of T2DM.10 Conversely, up-regulation of p53 in adipose tissue causes an inflammatory response that leads to IR. Using genetic models of ageing, including telomerase-deficient mice, it has been shown that p53 in adipose tissue is critically involved in IR.10 Telomerase-deficient mice with short telomeres developed IR when fed a high-calorie diet.10 The adipose tissue of these mice showed senescence-like changes, such as increases in the activity of senescence-associated β-galactosidase (SAβ-gal), level of expression of p53, and production of SASPs.10 Resection of senescent adipose tissue improved IR in telomerase-deficient mice, and implantation of senescent adipose tissue into wild-type mice led to impairment of insulin sensitivity and glucose tolerance in the recipients.10 Up-regulation of p53 induced the expression of SASPs and accumulation of macrophages in adipose tissue.10 These findings indicate that modulation of cellular ageing signals (e.g. p53 in adipose tissue) can up-regulate the expression of proinflammatory molecules, thereby promoting the infiltration of macrophages into adipose tissue, which leads to a further increase in the production of SASPs by the adipose tissue, which induces IR and glucose intolerance. This implies that cellular ageing signals in adipose tissue could be a new target for the treatment of age-related disease such as cardiometabolic disease. p53 activation in adipose tissue is an example of a pro-ageing signal that negatively regulates longevity. Thus, inhibition of adipose tissue ageing signalling can be an effective therapeutic strategy for ageing and its associated diseases. In this context, an alternative approach may be to replenish the aged adipose tissue by rejuvenating existing cells or injecting their cellular products, capable of supplying the ischaemic tissue with new vessels to prevent ischaemic tissue damage. Our research group has examined the interplay in adipose tissue-derived mesenchymal stromal cells (AT-MSCs) and in bone marrow-derived MSCs (BM-MSCs) between two genes, one coding for the catalytic subunit of telomerase (i.e. telomerase reverse transcriptase or TERT), that has antisenescence properties, and the other coding for myocardin (MYOCD), a nuclear transcription cofactor for myogenic genes, as well as for genes involved in muscle regeneration and protection against apoptosis.6 , 7 Our research group has examined the role of TERT and MYOCD in the conversion of aged MSCs to rejuvenated antiapoptotic, promyogenic stem cells.6 We have found that the delivery of the TERT and MYOCD genes can restore functionality of MSCs from aged mice, by increasing cell survival, proliferation, and smooth muscle myogenic differentiation in vitro.6 Furthermore, the therapeutic efficacy of these rejuvenated cells in an in vivo model of acute myocardial infarction has been demonstrated.11 Studies in humans that have analysed adipose tissue from age-, and T2DM-matched obese patients are limited and there are virtually no studies in patients with cardiovascular disease. The most comprehensive study to date is from the group of Gómez-Serrano, showing a global down-regulation of mitochondrial proteins related to both T2DM development and ageing progression.12 Using high-throughput proteomics and systems biology methods, this study showed down-regulation of proteins related to mitochondrial transport, energy metabolism, oxidative phosphorylation, and membrane organization in older vs. younger patients.12 In view of the importance of adipose tissue ageing in the genesis of cardiometabolic disease, there is the need to systematically assess T2DM and ageing differences in adipose tissue from patients with cardiovascular disease, in order to identify new biomarkers for the onset of cardiometabolic disease, as well as to gain insight into the influence of ageing in this disorder. Using a similar approach to ours but in a different mouse model of Hutchinson–Gilford Progeria Syndrome (HGPS; an accelerated ageing syndrome associated with premature vascular disease and death due to heart attack and stroke), investigators from the Methodist Research Institute in Houston led by John P. Cooke reported, in this issue of the European Heart Journal, on human TERT (hTERT) treatment of HGPS endothelial cells (ECs) which extends telomere length, restores endothelial function and gene expression, increases sirtuin 1 (SIRT1) expression, reduces markers of DNA damage, and extends life span.13 Such findings complement the previous reports on hTERT as the alternative target for age-related cardiovascular diseases. Such findings, therefore, might become an important experimental basis for reinforcing the translation of hTERT-based cell rejuvenation from basic science to clinical therapy in ischaemic cardiovascular diseases. Given the metabolic nature of atherosclerosis, a partial agenda for future research would be further complemented by large-scale, unbiased, global metabolomic and proteomic approaches capable of identifying multiple branches of the signalling networks activated by ageing in atherosclerotic disease and in the ischaemic heart, that might be successful in the search for novel diagnostic or therapeutic targets.14 The possibility of integrating different ‘omics’ approaches gives new hope to better understand the ischaemic heart signalling network and ‘diseasome’, to identify biomarkers for early diagnosis and follow-up of age-associated cardiovascular disease, and to better understand the molecular circuitry activated by ageing and leading to cardiometabolic disease. Identification of such mechanisms could lead to new treatment strategies for age-associated cardiovascular disease. This work was supported by a grant from Incyte to R.M. and funds from the Ministero dell’Istruzione, Università e Ricerca Scientifica to R.M. (549901_2020_Madonna:Ateneo). The funders had no role in the decision to publish, or preparation of, the manuscript. Conflict of interest: none declared. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.