**4. Thyroid function and ageing**

The relationship between thyroid function and ageing has been hypothesized more than one decade ago (Mariotti et al., 1995). Human ageing is associated with an increased prevalence of serum anti-thyroid antibodies and overt or mild thyroid dysfunction (Hollowell et al., 2002; Gharib et al., 2005a,b; Samuels, 1998; Tunbridge et al., 1977). Several clinical studies confirmed an age-dependent decrease of thyroid function including iodine uptake and thyroid hormone production (Hollowell et al., 2002; Gharib et al., 2005a,b; Samuels, 1998; Sawin et al., 2009; Tunbridge et al., 1977). Although there is a consensus on the detrimental effects of overt hypothyroidism in older patients, the clinical relevance of mild to moderate thyroid failure remains an uncertain area (Surks et al., 2004) and, animal models indicated that low thyroid hormones are associated to increased life span (Ooka et al., 1983). The relative small number of epidemiological studies with inappropriate statistical power, and the lack of large prospective randomized trials directed to evaluate the therapeutic effect and impact on survival of hormonal therapy in mild thyroid impairment, does not allow to conclude whether mild thyroid impairment is a favorable phenotype or a negative clinical condition, especially in older people. An age-dependent thyroid dysfunction (particularly hypothyroidism) has been well documented in the elderly, including the oldest-old population (>85 yr) (Helfand et al., 2004; Mariotti et al., 1993). An interesting study focused on thyroid function during physiological ageing was carried out by Mariotti et al. (1993). In this study thyroid status was assessed in 41 healthy centenarians and 33 healthy elderly subjects as compared to two control groups: 98 healthy normal adult subjects and 52 patients with miscellaneous non-thyroidal illness. Healthy centenarians showed a lower prevalence of positive anti-thyroid autoantibody titer than elderly controls with a relatively low (7%) prevalence of sHT although the median serum FT3 level was lower than in each other group. Interestingly, median serum TSH level of centenarians was lower than in healthy elderly subjects, in whom however, was significantly lower than in young controls (Mariotti et al., 1993). This study did not resolve the question whether the decreased FT3 and TSH value observed in healthy centenarians, represents an adaptive mechanism to reduced metabolic homeostasis or a protective condition in ageing. At partial odds with these data, a population based survey and one large cross-sectional study (Atzmon et al., 2009; Surks et al., 2007) showed a progressive shift of the normal serum TSH range towards higher values from healthy young individuals up to centenarians. Overall these data seem to suggest that ageing is associated with a certain degree of down regulation of the hypothalamuspituitary-thyroid-peripheral axis, although the clinical significance of such condition is far to be elucidated. To this regard, Rozing et al. (2010) reported that the offspring of nonagenarian siblings presented a lower thyroidal sensitivity to TSH and a paradoxical beneficial cardiometabolic profile as compared to their partners. The authors concluded that the favorable role of low thyroid hormone metabolism on health and longevity, already observed in animal models, might be applicable to humans as well. However, the study by Rozing et al. (2010) enrolled a specific population in order to identify familial determinants of healthy longevity in nonagenarian siblings. The results might, therefore, be affected by some bias and cannot be extended to the general population. On the other hand, a crosssectional study by Corsonello et al. (2010) carried out in 604 home-dwelling subjects born in Calabria (southern Italy), with ancestry in the region ascertained up to the grandparents, confirms a declining of serum thyroid hormone levels with ageing. Moreover, lower levels of FT3, FT4 and TSH were found in centenarians' children and nieces/nephews with respect to age-matched controls. Indeed, the authors conclude that an age-related subtle decline of thyroid function (either due to a familial component or due to a reset of the thyroid function occurring between the sixth and the eighth decade of life) seems to be related to longevity. Two other studies support the hypothesis that mild hypothyroidism in elderly might be associated to a better survival and performance status. In the first, Gussekloo et al. (2006) found lower all-cause and cardiovascular mortality in hypothyroid subjects aged more than 85 years followed for 4 years, when compared with euthyroid individuals. In the second, van den Beld et al. (2005) showed that low-serum T3 (with normal rT3) concentrations were associated with a better survival and physical performance, while subjects with low-serum T3 and high rT3 concentrations ("low T3 syndrome") did not show any survival advantage and had lower baseline physical activity. The authors suggested that higher serum rT3 concentrations may result from a decreased peripheral metabolism of thyroid hormones due to the ageing process itself and/or disease and may reflect a catabolic state although, a certain degree of lower activity of the thyroid hormone axis might be beneficial during the aging process.

186 Thyroid Hormone

The most common symptoms reported by sHT patients are the same although less evident than those observed in overt hypothyroidism: dry skin, poor memory, slow thinking, muscle weakness, fatigue, muscle cramp, cold intolerance, puffy eyes, constipation, and hoarseness (Canaris et al., 2000; Canaris et al., 1997). It is conceivable that clinical symptoms of hypothyroidism are related to the degree of thyroid failure, disease duration, and individual sensitivity to thyroid hormone deficiency (Biondi & Cooper, 2008). However, the presence of typical symptoms in patients with sHT remains controversial considering that many of them are non-specific and shared with many clinical conditions, especially in the elderly. Therefore, it is difficult to distinguish euthyroid subjects from sHT patients only by using clinical symptoms (Biondi & Cooper, 2008). Baseline data from a randomized clinical study confirmed a significant prevalence of hypothyroid symptoms among individuals with sHT (Cooper et al., 1984). Moreover, Canaris et al., (2000) reported fewer symptoms related to hypothyroidism in subclinical than in overt hypothyroid patients, but more frequently than in euthyroid controls. However, this study did not distinguish between treated or untreated subclinical and overt hypothyroid patients. By contrast, other crosssectional and case-control studies did not confirm these observations, but they were conducted among selected or referred populations often involving old hospitalized patients (Bemben et al., 1994; Zulewski et al., 1997). Age represents a confounding factor that may hinder the identification of symptoms of mild hypothyroidism: the typical findings of hypothyroidism are less common in the elderly and, if present, often either resemble or are attributed to chronic illnesses, drugs, depression or ageing *per se* (Billewitc et al., 1969; Samuels, 1998). Therefore, clinical signs and symptoms are poor predictors of sHT especially in the elderly; this fact may explain why the diagnosis of sHT, and sometime overt disease yet,

The relationship between thyroid function and ageing has been hypothesized more than one decade ago (Mariotti et al., 1995). Human ageing is associated with an increased prevalence of serum anti-thyroid antibodies and overt or mild thyroid dysfunction (Hollowell et al., 2002; Gharib et al., 2005a,b; Samuels, 1998; Tunbridge et al., 1977). Several clinical studies confirmed an age-dependent decrease of thyroid function including iodine uptake and thyroid hormone production (Hollowell et al., 2002; Gharib et al., 2005a,b; Samuels, 1998; Sawin et al., 2009; Tunbridge et al., 1977). Although there is a consensus on the detrimental effects of overt hypothyroidism in older patients, the clinical relevance of mild to moderate thyroid failure remains an uncertain area (Surks et al., 2004) and, animal models indicated that low thyroid hormones are associated to increased life span (Ooka et al., 1983). The relative small number of epidemiological studies with inappropriate statistical power, and the lack of large prospective randomized trials directed to evaluate the therapeutic effect and impact on survival of hormonal therapy in mild thyroid impairment, does not allow to conclude whether mild thyroid impairment is a favorable phenotype or a negative clinical condition, especially in older people. An age-dependent thyroid dysfunction (particularly hypothyroidism) has been well documented in the elderly, including the oldest-old

may be delayed in older people (Biondi & Cooper, 2008).

**4. Thyroid function and ageing** 

All together, these findings might support the idea that mild physiologically decline of thyroid activity at the tissue level might have favorable effects in the oldest-old subjects. However, the interpretation of the predictive value of thyroid failure in old subjects has to be considered with caution, carefully defining the context and the criteria of analyzed populations. In this setting, the comparison of observational trials is not so easy and the different population analyzed should be taken into account. Indeed, there is not a unique definition of TSH limits for patient classification in the clinical studies or statistical analysis, and the population of published trials is very heterogeneous differing for the age of enrolled patients, life styles, comorbidities, treatments, ethnics etc. Although in some selected elderly subjects (specific ethnic population or very old subjects) (subtle) thyroid failure might be a beneficial factor or a longevity associated character, one of the most debated issues regarding the health consequences of (subclinical) hypothyroidism in the elderly is represented by the potential increase of ischemic heart disease (IHD) or other CVDs as well as cognitive impairment (Mariotti et al., 2005).

Mild Thyroid Deficiency in the Elderly 189

increased risk of cardiovascular events, it is necessary to review the molecular effects of T3 and T4, and the modifications that they exert in myocytes, endothelium, vascular muscle cells, intermediate metabolism etc. The decrease of cardiac output associated with hypothyroidism results, in part, from changes in cardiac gene expression, specifically reduced expression of the sarcoplasmic reticulum Ca2-ATPase, and increased expression of its inhibitor, phospholamban (Belke et al., 2007). In addition, these molecular changes explain the prolonged isovolumic relaxation phase of the hypothyroid myocardium and early reversible diastolic impairment (Klein & Danzi, 2007). Interestingly, this mechanism functionally resembles the progressive age related myocardium modification, in which increased fibrosis, myocyte hypertrophy and myocyte loss result in increased myocardial

Triiodothyronine produces a decrease in systemic vascular resistance enhancing arteriole dilatation of the peripheral circulation (Klein & Ojamaa, 2001). The endothelium and smooth muscle cells are biological targets of action of T3 with a vasodilatation effect, also in coronary arteries (Ojamaa et al., 1996). As stated by Klein & Ojamaa (2001), T3 induces in vitro relaxation of smooth muscle cells with a non-genomic effect and independently of nitric oxide production (Klein & Ojamaa, 2001). Indeed, Ojamaa et al. (1996) found that the exposure of primary cultures vascular smooth muscle cells to T3 resulted in cellular relaxation within 10 min while, the exposure of primary cultures of vascular endothelial cells to the same hormone did not induce nitric oxide production, suggesting a direct effect of T3 on vascular smooth muscle cells. By contrast, Colantuoni et al. (2005) showed that *in vivo* thyroid hormone induced vasodilatation is delayed and mainly dependent to nitric oxide. The aim of their study was to assess the effects of topically applied T3 and T4 on the arterioles of hamster cheek pouch microcirculation *in vivo* by visualizing microvessels through a fluorescent microscopy technique. Topical application of both T3 and T4 consistently induced a dose-dependent dilation of arterioles within few minutes. However, T3-induced dilation was countered by the inhibition of nitric oxide synthase with specific *i*Nos inhibitors. These discrepancies between *in vitro* and *in vivo* findings might be related to differences in experimental procedures and to the fact that *in vivo* conditions are more complex than *in vitro* insolated cell cultures (Galli et al., 2010). The vascular action of T3 and T4 has been also reported to be associated with the modulation of gene expression related to endothelial homeostasis like angiotensin receptors (Fukuyama et al., 2003), reinforcing the hypothesis that thyroid hormones mainly target the vasculature. Accordingly, a cross-sectional study on 30728 patients without previous known thyroid diseases revealed a linear positive association between TSH level and systolic and diastolic blood pressure (Asvold et al., 2007). In this setting, Fommei et al. (2002) reported the physiological relationships between blood pressure and neuro-humoral modifications induced by acute hypothyroidism [levothyroxine (LT4) withdrawal] in normotensive subjects. During the hypothyroid state daytime arterial blood pressure (mainly diastolic) significantly increased along with noradrenaline and adrenaline levels. By contrast, plasma renin activity remained unchanged. These data, besides confirming the role of thyroid hormones in systemic arterial blood pressure homeostasis, suggest that sympathetic and adrenal reversible activation may contribute to the development

stiffness leading to diastolic heart failure (Biondi & Cooper, 2008).

of arterial hypertension in human hypothyroidism (Fommei et al., 2002).
