Current Aging Science (v.9, #1)

Meet Our Editorial Board Member by Ashok K. Shetty (1-1).

Daily Melatonin Administration Attenuates Age-Dependent Disturbances of Cardiovascular Rhythms by Denis G. Gubin, Gennady D. Gubin, Ludmila I. Gapon, Dietmar Weinert (5-13).
Increased blood pressure and reduced robustness of circadian rhythms are frequently reported in elderly subjects. The present study was aimed to investigate whether such changes can be reversed by daily melatonin ingestion. 97 normotensive and hypertensive volunteers of both genders and 63 to 91 years old participated. They lived in the Tyumen Elderly Veteran House on a self-chosen sleep-wake regimen to suit their personal convenience. The experiment lasted for three weeks. After one control week, part of the group (n=63) received 1.5 mg melatonin (MelaxenTM) each day at 22:30 h for two weeks. The other 34 subjects were placebo-treated. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured using semi-automated devices at 03:00, 08:00, 11:00, 14:00, 17:00, 23:00 h each day of the first and the third week. Specially trained personnel made the measurements, taking care not to disturb subjects' sleep. Rhythm characteristics were estimated by means of single and population-mean cosinor analyses. Bingham test was used to compare rhythm parameters between groups and investigated physiologic variables.
The 24-h HR rhythm was monophasic as described in other studies for young subjects though with a steeper increase in the morning. The daily SBP and DBP rhythms were bimodal. In reference to previously reported data of younger subjects, mean blood pressure of our cohort was elevated, particularly the nocturnal fall was less pronounced. Also, the overall SBP variability was higher as was the percentage of the 12-h component. Both values and also the SBP and DBP levels were reduced during melatonin treatment. The hypotensive effect of melatonin was most pronounced between 3:00 and 8:00 in the morning, i.e. at the time of the highest risk of adverse cardiovascular events, and in subjects with highest BP values before treatment. Moreover, the morning increase of HR was gentler what could have been of additional benefit.
Melatonin has a direct hypotensive effect. Also, it stabilizes the internal temporal order enhancing the circadian component and the synchronization between rhythms of different physiological functions. This may further improve health and welfare of elderly subjects and particularly of those with hypertension. Taken together our data show the usefulness of melatonin for adjuvant medication.


Age-Dependent Changes of the temporal Order - Causes and Treatment by Denis G. Gubin, Dietmar Weinert, Tatyana V. Bolotnova (14-25).
This review summarizes current knowledge on deteriorations in temporal order with advanced age. Changes of the overt rhythms will be described but also their putative causes and possible treatments of the disturbances. In aging animals and humans, all rhythm characteristics change. The most prominent changes are a decrease of circadian amplitude, leading to an extra-circadian dissemination (ECD), and a diminished ability to synchronize with the periodic environment.
ECD is a shift from circadian to ultradian and infradian frequencies, accompanied by the loss of day-to-day phase stability. Responsiveness to photic and non-photic cues is decreased. As a consequence, both internal and external temporal order are disturbed not only under steady-state conditions but and even more markedly after changes in the periodic environment or following stressful events.
Many of the changes seem to occur within the suprachiasmatic nucleus (SCN), the central circadian pacemaker, itself. The number of functioning neurons decreases with advancing age as does the coupling between them. Accordingly, the SCN generates a weaker and less stable circadian signal, insufficient to entrain peripheral oscillators properly or to regulate body functions rhythmically. However, age-dependent disturbances in peripheral organs must also be considered. These changes may occur at different ages, thus causing further internal desynchronization.
Several possibilities exist with regard to treating circadian disruptions or at least minimizing their consequences for health and fitness and preventing sleep disturbances. Benefits of bright light, melatonin and other chronobiotics, physical activity, social contacts and regular feeding schedules in preserving the temporal order of aged organisms are discussed.

Age-Related Sleep Changes and its Implication in Neurodegenerative Diseases by Elena A. Lyashenko, Michael G. Poluektov, Oleg S. Levin, Polina V. Pchelina (26-33).
In the article authors discuss the current data on sleep changes with aging focusing on the influence of age-related degenerative changes in orexin-containing and pacemaker brain areas. Pathophysiological mechanisms of sleep disturbances in Parkinson's and Alzheimer's diseases have much in common with normal age neurophysiological changes. Maintenance of the sleep-promoting systems function could positively modify the course of these diseases.

Aging is associated with a marked increase in sleep complaints, and one factor causing sleep disruption is waking to void (nocturia). Urological surveys have found that few young adults report nocturia symptoms, but about half of those in their 60's and nearly 80% of older age groups are affected. Sleep surveys have found nocturia is a major cause of sleep disruption, with a majority of older adults with sleep disruption citing the need to void as the cause of their awakening. While much of the urological literature implies that nocturia causes sleep disruption, age-related changes in sleep depth and continuity may make it more likely that an older adult will wake in response to a filling bladder, or that an older adult will wake for another reason and then decide to void. There is also evidence that age-related changes in the amplitude of circadian rhythms contribute to nocturia. There is a well-described circadian rhythm in urine output, and evidence of circadian rhythmicity in some diuretic and anti-diuretic hormones. In this article, we describe how age-related changes in sleep depth and continuity and age-related changes in circadian rhythm amplitude may contribute to nocturia, and how nocturia in turn leads to sleep disruption. Better understanding of how changes in sleep and circadian rhythmicity impact nocturia may lead to improved treatments and better quality of life for older adults.

The aging process is often associated with more or less prominent shifts of the entrained phases of behavioral and physiological rhythms at earlier clock hours, but the oscillatory mechanisms underlying these shifts have to be determined. The analysis of self-reports on home sleep times and self-scorings of sleepiness provided by 130 participants of sleep deprivation experiments revealed the difference between intro-individual (age-related) and inter-individual (gender- and chronotype-related) variation in phase angle between sleep timing and timing of nocturnal rise of sleepiness. A heterochronity of age-related changes in phase characteristics of the circadian rhythms was suggested for explaining this difference. In particular, a rhythm's strength might determine the rate of age-related decline of its entrainment mechanism. In the case of a weak circadian rhythm, such as the homeostatic process underlying oscillations of slow wave activity in the sleep-wake cycle, a decline of the rhythm's strength might be already pronounced in middle aged adults. In contrast, a similar decline might occur much later in the cases of the homeostatic processes underlying stronger rhythms, such as the fluctuations of alertness-sleepiness, body temperature, melatonin secretion, etc. Moreover, the strength of a strong rhythm might become weaker earlier than that of the circadian pacemaker and, especially, earlier than decline of its ability to entrain to the light-dark cycle. Such sequence of changes in the circadian entrainment mechanisms might explain a general tendency to produce advance rather than delay shifts of entrained phases of circadian rhythms with progression of age from middle adulthood to elderly.

Lower Frequency of co-Morbid Medical Disorders Related to Poor Impulse Control in Parkinson's than Alzheimer's Disease by Erin K. Saito, Natalie Diaz, Julia Morrow, Julia Chung, Aaron McMurtray (57-60).
Parkinson's disease is associated with progressive degeneration of mesolimbic dopaminergic neurons that are involved in reward-based behavior learning, including rewarding effects of food consumption and drugs of abuse. The importance of this pathway in development of addictive behaviors led us to hypothesize that medical disorders related to poor impulse control may occur less frequently among patients with Parkinson's disease than those with other progressive neurodegenerative disorders such as Alzheimer's disease. Retrospective cross-sectional study of all patients treated for Parkinson's disease and Alzheimer's disease in a community based clinic during a two-year period. Associations were summarized using odds ratios (OR) and 95% confidence intervals (95% CI) estimated from logistic regression models, adjusted for differences in gender distribution between the groups. A total of 106 patients with Parkinson's disease and 72 patients with Alzheimer's disease were included. Patients with Parkinson's disease were less likely to have either past substance use (adjusted OR = 0.035, 95% CI = 0.009 - 0.130) or presence of co-morbid medical conditions related to poor dietary choices (adjusted OR = 0.157, 95% CI = 0.062 - 0.397). Co-morbid medical conditions related to poor impulse control occur less frequently among those with Parkinson's disease than those with Alzheimer's disease. These findings are consistent with dysfunction of dopamine dependent pathways involved in addiction during the presymptomatic phase of Parkinson's disease and support a biological basis for addiction.

Huntington's disease (HD) is a progressive fatal dominant hereditary neurodegenerative disease of the brain, which primarily affects the cortex and the striatum. The disorder is typified by an expansion of more than 35 repeats of the nucleotide triplet cytosine- adenine-guanosine (CAG) which codes for the amino acid glutamine in the huntingtin gene. Despite studies of several decades, there are no effective means to block or postpone the appearance of symptoms of HD. Analysis of these studies led us to propose that increased oxidative stress and chronic inflammation are earliest events in the pathogenesis of HD, and together with excessive glutamate release, participate in the progression of the disease. This review briefly describes evidence for the involvement of oxidative stress, chronic inflammation and glutamate in the pathogenesis of HD. It is proposed that attenuation of these biochemical abnormalities together, may delay the appearance of symptoms of HD. In order to achieve this goal, the simultaneous activation of the nuclear transcriptional factor-2/antioxidant response elements (Nrf2/ARE) pathway that would enhance the transcription of target genes coding for antioxidant enzymes and phase-2-detoxifying enzymes, and an elevation of the levels of antioxidant compounds by supplementation may be needed. Normal mechanisms of activation of Nrf2 requiring reactive oxygen species (ROS) may be impaired in HD, but certain antioxidant compounds can activate Nrf2 without ROS. Use of a combination of micronutrients that can activate the Nrf2/ARE pathway and enhance the levels of antioxidant compounds is suggested.

Changes in respiratory function are common in older populations and affect quality of life, social relationships, cognitive function and functional capacity. This paper reviews evidence reported in medical and psychological journals between 2000 and 2014 concerning the impact of changes in respiratory function on daily living in older adults. A tentative model establishes relationships involving respiratory function, cognitive function and functional capacities. The conclusion stresses the need for both longitudinal studies, to establish causal pathways between respiratory function and psychosocial aspects in aging, and intervention studies.

Erratum (77-77).