Immune Function as a Biomarker of Age and Predictor of Remaining Life Expectancy
The immune system declines with age, as the proportion of its cells capable of responding to new threats falls, autoimmunity increases, and the system as a whole enters a state of constant, rising inflammation. The failure of the immune system speeds other forms of damage and dysfunction in aging, as immune cells are responsible for killing potentially harmful cells, such as those that become senescent or precancerous. The immune system also plays important roles in a variety of essential processes, such as wound healing and maintenance of brain tissues. Clearing out the causes of immune system decline will be a necessary part of any future toolkit of rejuvenation therapies. The open access paper linked here is an illustration of the importance of immune function in aging, as markers of its decline correlate with age and remaining life expectancy:
Chronological age, defined as the time elapsed since birth, fails to be an accurate indicator of the rate of the aging process. This is due to the heterogeneity that aging shows in the diverse members of a population. This phenomenon led to the concept of "biological age", which estimates how well an individual functions in comparison with others of the same chronological age. Given that biological age is a better indicator than chronological age of the health, remaining healthy life span, and active life expectancy of each subject, its determination is very relevant. However, despite its simple definition, quantification of the biological age is a difficult task. Many studies have been carried out trying to obtain the most appropriate parameters for determining biological age and have been mainly focused on both physiological (respiratory function, systolic arterial tension) as well as on biochemical (albumin, cholesterol) markers. Moreover, other markers such as genetic (telomere length) or epigenetic (DNA methylation) have also been proposed. Nevertheless, despite different sets of markers being proposed in these studies, none of them have been validated. Therefore, the subject is still incomplete and more research should be carried out.
Most work on biological age has not included parameters of the immune system, which is a homeostatic system that contributes to the appropriate function of the organism. It is well known that with aging there is an increased susceptibility to infectious diseases, autoimmune processes and cancer, which indicates the presence of a less competent immune system, exerting a great influence on age-related morbidity and mortality. Since it has been demonstrated that the functioning of the immune system is an excellent marker of health and given that several age-related changes in immune functions have been linked to longevity whereas others have been shown to be predictive of mortality, the aim of the present study was to determine if some immune functions could be useful as markers of biological age and therefore as predictors of longevity.
In order to validate a potential set of parameters as markers of biological age, it is necessary to confirm that the levels shown in particular subjects reveal their real health and senescent conditions and, consequently, their rate of aging. This has to be demonstrated by meeting two requirements. The first is that if an adult individual shows values characteristic of a chronologically old individual, he or she should die prematurely. The second is that a long-lived individual, known to have experienced healthy aging, should have a value of these biomarkers similar to that of an adult. The first requisite can only be confirmed in experimental animals, given that it is a difficult task to follow-up human subjects throughout the whole aging process due to their long life span. Thus, mice were chosen for our study, which show a mean longevity of about 2 years. The second requirement can be confirmed in both human centenarians and experimental animals such as extremely long-lived mice.
Among all the possible functions of immune cells, we have focused on the ones that are the most relevant in the immune response and are known to experience an age-related decrease. In phagocytes, their ability to migrate towards the focus of infection (chemotaxis) and their capacity to ingest foreign particles (phagocytosis); in natural killer (NK) cells, their capacity to destroy tumoral cells and in lymphocytes, their ability to migrate towards the site of antigen recognition (chemotaxis) and to proliferate in response to mitogens (lymphoproliferation). Thus, in order to validate the above mentioned immune functions as markers of biological age and predictors of longevity, these functions were studied in leukocytes isolated from peripheral blood of human subjects in a cross-sectional study, from their 30s until their 100s. In addition, the same functions were analyzed in leukocytes obtained from peritoneum of mice without killing them, enabling a longitudinal study to be performed, starting at the adult age and following each animal until its death. Neutrophil chemotaxis and phagocytosis, as well as the activity of NK cells, lymphocyte chemotaxis and proliferative response showed lower values in old individuals in comparison to those in adults. Considering the state of these functions in subjects which reach a high longevity, and consequently have attained successful aging, both humans and mice showed more similar values to those observed at adult age than to those at old age.