The Aging Thyroid: A Reappraisal Within the Geroscience Integrated Perspective.

The thyroid plays a crucial and pervasive role in physiology (metabolism, thermogenesis, and immunity, among others) and its aging and related changes in thyroid hormone production contribute to the common occurrence of thyroid diseases in elderly and to age-associated changes in other organs and systems. We address the complexity of thyroid aging following the basic suggestions of geroscience. This integrative new perspective identifies a few basic molecular mechanisms or "pillars" (inflammation, adaptation to stress, loss of proteostasis, stem cell exhaustion, metabolism derangement, macromolecular damage, and epigenetic modifications) as a unifying conceptual framework to understand the aging process and age-associated diseases. Within this scenario, we review available data on the presence and role in the thyroid of alterations of such mechanistic pillars, paying particular attention to (i) inflammation, focusing on cellular senescence and age-associated dysbiosis (alteration of gut microbiota); (ii) telomere shortening as an example of macromolecular damage; (iii) proteasomal function, including mitophagy and autophagy; (iv) stem cells and cell renewal; (v) energy metabolism and mitochondrial dysfunction; and (vi) age-related epigenetic changes, focusing on DNA methylation. Overall, the study of these topics in the thyroid is in its infancy and deserves much more attention. Finally, thyroid function in centenarians as a model of healthy aging is reviewed within the framework of possible adaptive mechanisms involving the thyroid to attain longevity. Accordingly, the concept of "thyroid biography" is proposed to grasp the complex combination of factors (including endocrine disruptors and lifestyle habits) impinging lifelong on thyroid function at the individual level.