Age-related diseases began as a matter of taxonomy. Presented with the immensely complex, mysterious, varied, and inscrutable happenings at the end of life, the first scientists, before science was even much defined, began by trying to categorize their observations. Categorization is the first step towards making sense out of the unknown. Some forms of decline are obviously similar. Some are much worse than others in characteristic ways. Common manifestations are bucketed and given names: dementia, apoplexy, dropsy. These named facets of aging then became diseases just about as soon as people started to think that they could be treated - rightly or wrongly, and largely wrongly. The slow carving away of slivers of the inscrutable core of aging, making them known, and attempting to treat them, naturally gave rise to the idea that there existed aging, and separately there existed diseases of aging, states that were somehow distinct.
This mistaken belief has persisted into our era, in which the classification of age-related disease has become highly formal, regulated, and detailed. Aging is still not considered a medical condition to be treated, though the battle to change this state of affairs is progressing, and it requires years to create a new formal definition of age-related disease. The mainstream still proceeds by carving diseases from the bulk of aging, one by one, just as soon as mechanisms are understood to the point at which forms of therapy can be proposed. Sarcopenia is one of the most recently named diseases of aging, and it is still undergoing formalization a decade after that process started. Without that formal, regulatory blessing, clinical development of therapies proceeds in only a limited fashion because it would be illegal to offer commercial therapies. There is so much inertia in this wasteful edifice of medical taxonomy that to break away to a better understanding and approach will require a major, long-running project of advocacy to reeducate the establishment.
There is such a thing as a wrong question: a question that arrives with a baggage of incorrect axioms, and to take it a face value is to be misdirected before even investigating a potential answer. To ask when the changes of aging become the pathology of disease is one such question. Yet that has been asked and answered for every formally defined age-related disease. It is built on a faulty view of aging, that the causative mechanisms of aging can be something other than pathological. But all aging is damage, even the damage that hasn't yet risen past minor inconvenience to the level of great pain, disability, and frailty. It is the same cell and tissue damage, and the current outcome is just a matter of degree. The most effective therapies will target that damage, but by drawing lines that don't exist between aging and disease, much of the research, medical, and regulatory communities have sabotaged and continue to sabotage their efforts to make a difference.
This paper is one example among many of researchers engaging with this model of thinking. It leads only to confusion - the inevitable destination for any attempt to split causation in aging into pathology and not-pathology, to find a definite transition from something innocuous to the malign cause of a disease state. At root it is all pathology: metabolism produces damage, damage produces aging, and the causes of aging start just as soon as metabolism starts. After that it is all just a matter of how damaged an individual happens to be. The more damage, the greater the disability, the higher the mortality rate. It is one unified, complex process, driven by the comparatively simple injection of molecular damage. Treating aging effectively can be as straightforward as working to address and reverse the damage, at any stage, however much of it there might be. The earlier the better.
The true onset of atherosclerosis remains one of the biggest challenges for cardiologists. Is atheroma plaque development considered the earliest step of vascular aging? If so, when does it start? Before or after birth? If it starts before birth or early during childhood, it seems that Thomas Sydenham was right: "A man is as old as his arteries." Except disorganization of elastic fibers, less is known about the morphology of vascular aging and also about the molecular events influencing the age of arteries, arterial stiffness, and their role in the appearance of future complications. Cellular and molecular events responsible for the switch from physiologic to pathologic aging of human arteries are less known.
Vascular aging is described as a gradual process involving biochemical, enzymatic, and cellular events in vascular area combined with epigenetic and molecular alterations, and it is considered that arterial aging is a fundamental reflection of biological aging in general and a determinant of organ function. In the arterial wall, this is characterized by a decrease of elastin content, as well as by the production and accumulation of "bad" collagen and its cross-linkages, leading to increased arterial stiffness and elevated central blood pressure as well as brachial blood pressure, accompanied by increased variability in systolic blood pressure (SBP). A better understanding of these processes has led to the proposal of a condition named early vascular aging (EVA) in patients with increased arterial stiffness for their age and sex. This is a condition that could increase cardiovascular risk, and it is associated with various degrees of cognitive dysfunction, as well as other features of biological aging.
It is considered that vascular aging is found from several and sequential alterations that lead to the replacement of elastin fibers with collagen fibers in the vessel wall, which forms a less elastic structure due to the collagen bridges that prevent their elongation. This is the so-called physiological arterial stiffness. In time, there may be a pathological aging, consisting of various types of plaque deposition. There is no well-defined criteria that characterize EVA in this moment. What seems to be "early" for clinicians may be "too late" stages of vascular aging for vessel wall and also for the patient. "Early" microscopic changes in the structure of the arterial wall do not overlap with "early" vascular aging definition and assessment at all!
Data regarding the assessment of early steps of aortic wall changes and atheroma plaque formation are scattered for prenatal period, childhood, and teenage years. It is suggested that EVA starts in fetal life as stated by a few papers reporting perinatal atherosclerotic lesions in the fetal coronary arteries of babies of mothers who are smokers or by data suggesting the involvement of telomere length influencing arterial function and aging properties which could be programmed during fetal life or influenced by adverse growth patterns in early postnatal life.
The mechanism of vascular aging is associated with changes in the mechanical and structural properties of the arterial wall. These changes lead to the loss of arterial elasticity and reduced compliance because of the changes in the ratio between elastin and collagen fibers. Over time, destruction of elastin fibers with linear parallel structure takes place, due to the so-called fatigue phenomenon of the elastin. This leads to the breaking and fragmentation of elastin fibers which are replaced in a higher ratio with collagen fibers, resulting in a structure with increased rigidity.
The beginning of elastic fiber loss or damage remains a questionable issue for cardiologists. Our preliminary data showed that disorganization of elastic fibers appears early in human fetal aorta and continues during postnatal life, being extended immediately after birth. The process is not homogeneous along all length of the fetal or neonatal aorta, being mostly and easily detected on aortic arch level in prenatal life and immediately after birth. In this context, a big challenge is launched: how and when to define EVA related to detected microscopic changes which, for sure, anticipate the beginning of clinical vascular aging. Due to these facts, arterial stiffness may be seen as a complication of true, microscopic EVA.
If we would abruptly make a conclusion of the present review, we should go back to Thomas Sydenham who stated that "A man is as old as his arteries." This is definitely true but, unfortunately, it does not help patients to decrease vascular aging and to improve their life quality. Recently, it was suggested that the dissociation between chronologic and biologic age of large arteries represents the main reason for the failure of proper definition of EVA which overlaps clinical signs and patient prognosis. There are few studies regarding the molecular mechanisms of EVA with emphasis to the activation of pro-fibrotic, pro-inflammatory, redox-sensitive, and growth/apoptotic signaling pathways, but most of these studies were developed in mice and not yet validated in human subjects.