Abstract
An inverse correlation between thyroid hormone levels and longevity has been reported in several species and reduced thyroid hormone levels have been proposed as a biomarker for healthy aging and metabolic fitness. However, hypothyroidism is a medical condition associated with compromised health and reduced life expectancy. Herein, we show, using wild-type and the Pax8 ablated model of hypothyroidism in mice, that hyperthyroidism and severe hypothyroidism are associated with an overall unhealthy status and shorter lifespan. Mild hypothyroid Pax8 +/- mice were heavier and displayed insulin resistance, hepatic steatosis and increased prevalence of liver cancer yet had normal lifespan. These pathophysiological conditions were precipitated by hepatic mitochondrial dysfunction and oxidative damage accumulation. These findings indicate that individuals carrying mutations on PAX8 may be susceptible to develop liver cancer and/or diabetes and raise concerns regarding the development of interventions aiming to modulate thyroid hormones to promote healthy aging or lifespan in mammals.
Highlights
The increasing burden of age-related diseases highlights the importance of uncovering the mechanisms underlying the aging process
Necropsy revealed that Pax8 +/- mice were susceptible to develop with age liver cancers with hallmarks of hepatocellular carcinoma, as no gross anatomical alterations were detected at day 21 of life
Our study only included male mice, representing a limitation of our work, we provide evidence that either the lack or chronic supplementation of thyroid hormone (TH) reduces life expectancy while mild hypothyroidism compromises healthspan without extending lifespan
Summary
The increasing burden of age-related diseases highlights the importance of uncovering the mechanisms underlying the aging process. Greater life expectancy has been associated with reduced circulating levels of T4, T3, and/or high TSH levels in both, animal models and humans [3, 5,6,7,8]. Epidemiological observations have indicated that, both hypothyroidism and subclinical hypothyroidism, are serious medical conditions associated with cardiovascular problems and several metabolic disorders, such as steatosis and cancer, that reduce health and increase mortality risk [28,29,30,31] These contradictory observations led us to assess the specific effect of the modulation of TH levels in murine healthspan and lifespan using the Pax knock-out animal model of hypothyroidism (Wild type [Wt], Pax8 +/- and Pax8 -/-) supplemented or not with THs
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