and activate β1 adrenergic receptors causing strengthening of the heart contractions (Wingerd et al., 2004). In addition, altered adrenergic innervation to the heart has been implicated in sudden cardiac death following myocardial infarction (Chen et al., 2001). Furthermore, the maintenance of neuronal numbers in the SCG by trophic factors such as nerve growth factor (NGF) is necessary to ensure proper function of the target tissues innervated by the SCG. For example, the levels of NGF decline with advancing age, however, the trophic response of perivascular sympathetic nerves to NGF is preserved (Isaacson & Crutcher, 1998; Dickason & Isaacson, 2002). Thus, the response to NGF during the aging process may have implica- tions for the function of target organs innervated by the SCG (reviewed by Cowen & Gavazzi, 1998). Overall, the evidence in terms of normal aging argues that peripheral neurones attempt to maintain homeostasis and can respond to trophic influences later in life. In the rat cerebrovasculature, adrenergic and sensory inner- vation is fully developed within the first 30 days of life (Tsai et al., 1989). Specifically, in the cerebrovasculature adrenergic innervation influences the development of cerebral blood vessels and their motor function, as their presence is necessary for angio- genesis and the modulation of contractile function. For example, in rabbits aged 3–20 weeks, removal of the SCG results in loss of vascular smooth muscle mass, reduced wall thickness and attenuated contractility (Bevan & Tsuru, 1981). In addition to the cardiovascular regulatory effects of the SCG, it also plays a role in protecting the cerebrovasculature from stroke. Hemorrhagic stroke accounts for about 10% of cerebrovascular disease with a peak incidence near the age of 60 years and high probability of morbidity or mortality. Risk factors for stroke include age-related hypertension and changes in the structure of cerebral blood vessels (Abbott et al., 2003; Zhang et al., 2003; Lawes et al., 2004). Numerous mechanisms contribute to regulation of cerebral blood flow and modulate blood vessel wall tension (Faraci & Heistad, 1998; Zhang et al., 2003). Spontaneous constriction of blood vessels in response to increased blood pressure from 60 to 140 mmHg is called myogenic tone or autoregulation, which reduces wall tension and risk of blood vessel rupture. At systolic pressures, above 140 mmHg myogenic response alone can no longer control wall tension, and activation of adrenergic nerves arising from the SCG provides additional constrictor response to protect the cerebrovasculature from ruptured blood vessels (Van Riper & Bevan, 1991; Faraci & Heisted, 1998; Furuichi et al., 1999). More recent studies on how neural input regulates cerebrovas- cular tone and blood flow have resulted in the rediscovery of the ‘neurovascular unit’. These studies suggest that the combi- nation of neuronal input into smooth muscle and the inherent contractile properties of smooth muscle provide for the opti- mum function of cerebral blood vessels (reviewed by Hamel, 2006). Given that adrenergic nerves arising from the SCG inner- vate numerous organs including the cerebrovasculature and the importance of their homeostatic modulatory function, our group has chosen to focus our aging studies on this neuronal model. Age and Ca2+ homeostasis in peripheral neurones, J. N. Buchholz et al. 287 Overview of aging and calcium regulation in neurones Aging in all creatures is inexorable and has been suggested to be a combination of developmental changes, genetic defects, environmental influences, and an inborn genetic aging process (Harman, 1998; Guarente & Kenyon, 2000; Clancy et al., 2001; Tatar et al., 2001; Troen, 2003). These studies suggest that basic metabolism and ability to control accumulation of oxidants as well as genetic control pathways are involved in the aging process. For example, caloric restriction prolongs lifespan and reduces age-related morbidity and organ pathology (Bodkin et al., 2003; Forster et al., 2003). Overall, studies on caloric restriction, reduced oxidative stress, and lifespan render little explanation of age- related changes in the function of critical organ and neuronal systems, and little is known about the vulnerability of particular physiological processes to advancing age. Given that calcium acts as a universal second messenger in neurones, subtle age-related declines in mechanisms that modulate stimulation-evoked increases in [Ca2+]i have been hypothesized to contribute to age-related neuronal dysfunction and degeneration (Kirischuk & Verkhratsky, 1996; Verkhratsky & Toescu, 1998). In particular, one potential mechanism of calcium-mediated cell death suggests that calcium overload results in mitochondrial dysfunction leading to mitochondrial calcium overload and activation of caspases that mediate cell apoptosis (Ichas & Mazat, 1998; Thibault et al., 1998; Begley et al., 1999). An important issue in aging studies is a tendency to assume a general age-related deterioration of calcium regulatory processes leading to increased susceptibility to pathology and cell death (Porter et al., 1997). This assumption does not take into account compensatory mechanisms that serve to regulate [Ca2+]i homeo- stasis, thus maintaining some degree of neuronal function in senescent neurones or during acute insults such as stroke (Murchinson & Griffith, 1998; Verkhratsky & Toescu, 1998; Lee et al., 1999; Griffith et al., 2000; Pottorf et al., 2000a, 2002). Studying normal aging uncomplicated by disease holds the most promise in trying to understand the aging process under normal circumstances. Aging and alterations in control of neurotransmitter release in adrenergic neurones: multiple mechanisms The risk of stroke increases with age, and the single most impor- tant factor is rising systolic blood pressure (Faraci & Heisted, 1998; Abbott et al., 2003; Zhang et al., 2003; Lawes et al., 2004). Systolic blood pressure rises in both F344-Rats and in humans and is associated with increased plasma catecholamine levels suggesting that there is a fundamental age-related change in the function of peripheral adrenergic nerves (Palmer et al., 1978; Esler et al., 1981; Barnes et al., 1982; Yu et al., 1985; Insel, 1993). This concept is supported by studies showing that stimulation-evoked fractional release increases with age in arteries studied in vitro. These include the rat tail artery and © 2007 Loma Linda University Journal compilation © Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland 2007