Studies in humans suggest that lifestyle factors can have a beneficial impact on the risk for developing cognitive decline and dementia with age. There is growing evidence that maintaining a physically and intellectually active lifestyle can positively impact cognitive ability in older individuals. Dietary factors, such as the intake of antioxidants, may also prevent age-related cognitive decline. However, studies in humans are challenging; many variables cannot be controlled, making it difficult for researchers to determine the exact types and quantities of enrichment and dietary factors necessary for positive effects on cognition. Studies in animal models of human aging allow researchers to precisely control such variables, and can be used to assess the mechanisms and molecular pathways underlying any positive effects. Here we review the results of an intervention study using a canine model of human aging. The study was unique in that it compared the effects of dietary antioxidant supplementation alone and in combination with behavioral enrichment. We found that both interventions lead to improvements in cognitive ability in aged dogs; however, combining the treatments preserved cognition to a greater extent than either treatment alone. Overall, the results suggest that antioxidant supplementation and behavioral enrichment target separate yet complementary molecular pathways to improve cognition, and support the idea that combinations of treatments to improve cognition and slow brain aging will produce greater benefits than single interventions.

Chronological lifespan (CLS) is defined as the duration of quiescence in which normal cells retain the capacity to reenter the proliferative cycle. This study investigates whether hydroxytyrosol (HT), a naturally occurring polyphenol found in olives, extends CLS in normal human fibroblasts (NHFs). Quiescent NHFs cultured for a long duration (30–60 days) lose their capacity to repopulate. Approximately 60% of these cells exit the cell cycle permanently; a significant increase in the doubling time of the cell population was observed. CLS was extended in quiescent NHFs that were cultured in the presence of HT for 30–60 days. HT-induced extension of CLS was associated with an approximately 3-fold increase in manganese superoxide dismutase (MnSOD) activity while there was no change in copper–zinc superoxide dismutase, catalase, or glutathione peroxidase protein levels. Quiescent NHFs overexpressing a dominant-negative mutant form of MnSOD failed to extend CLS. HT suppressed age-associated increase in mitochondrial ROS levels. Results from spectroscopy assays indicate that HT in the presence of peroxidases can undergo catechol–semiquinone–quinone redox cycling generating superoxide, which in a cellular context can activate the antioxidant system, e.g., MnSOD expression. These results demonstrate that HT extends CLS by increasing MnSOD activity and decreasing age-associated mitochondrial reactive oxygen species accumulation.

Progressive telomere shortening with aging was studied using normal esophageal mucosal specimens from 177 human subjects aged between 0 and 102 years (yrs). We observed age-related shortening of the telomere, at a rate of 60 base pairs (bp) per year (yr). The mean telomere length of 12 neonates was 15.2 kilobase pairs (kbp) and that of 2 centenarians was 9.3 kbp. Mean (±SD) telomere lengths were 14.9±1.3, 14.0±1.8, 10.1±3.7, 10.4±3.3 and 9.5±3.1 kbp for the age groups less than 2 yrs, 2–20 yrs, 21–60 yrs, 61–80 yrs and 81–102 yrs, respectively. The variation in telomere length among individuals in the same age group was greater for the 3 older groups than for the 2 younger groups, as shown by the SDs. Furthermore, older individuals had greater telomere length variation than younger individuals, based on the lengths of DNA digested smears. Although the telomere length decreased significantly with aging at the rate of 60 bp per yr, differences in the mean telomere lengths between the 3 older age groups were not significant. Rapid shortening occurred in the young generations and there was no further substantial decrease in the esophageal mucosa after 60 yrs of age. Compared to the very rapid renewal rate of the esophageal epithelial cells, the annual reduction rate in telomere length was very low. These findings support the hypothesis that germ cells in the esophageal epithelium have a mechanism to lengthen telomeres.

Recent studies have shown that renin–angiotensin system overactivation is involved in the aging process in several tissues as well as in longevity and aging-related degenerative diseases by increasing oxidative damage and inflammation. We have recently shown that angiotensin II enhances dopaminergic degeneration by increasing levels of reactive oxygen species and neuroinflammation, and that there is an aging-related increase in angiotensin II activity in the substantia nigra in rats, which may constitute a major factor in the increased risk of Parkinson’s disease with aging. The mechanisms involved in the above mentioned effects and particularly a potential angiotensin–mitochondria interaction have not been clarified. The present study revealed that activation of mitochondrial ATP-sensitive potassium channels [mitoK(ATP)] may play a major role in the angiotensin II-induced effects on aging and neurodegeneration. Inhibition of mitoK(ATP) channels with 5-hydroxydecanoic acid inhibited the increase in dopaminergic cell death induced by angiotensin II, as well as the increase in superoxide/superoxide-derived reactive oxygen species levels and the angiotensin II-induced decrease in the mitochondrial inner membrane potential in cultured dopaminergic neurons. The present study provides data for considering brain renin–angiotensin system and mitoK(ATP) channels as potential targets for protective therapy in aging-associated diseases such as Parkinson’s disease.

Frailty is a multidimensional geriatric syndrome characterised by a state of increased vulnerability to disease. Its causes are unclear, limiting opportunities for intervention. Age-related changes to the immune-endocrine axis are implicated. This study investigated the associations between the immune-endocrine axis and frailty as well as mortality 10 years later among men and women aged 65 to 70 years. We studied 254 participants of the Hertfordshire Ageing Study at baseline and 10-year follow-up. At baseline, they completed a health questionnaire and had collection of blood samples for immune-endocrine analysis. At follow-up, Fried frailty was characterised and mortality ascertained. Higher baseline levels of differential white cell counts (WCC), lower levels of dehydroepiandosterone sulphate (DHEAS) and higher cortisol:DHEAS ratio were all significantly associated with increased odds of frailty at 10-year follow-up. Baseline WCC and cortisol:DHEAS clearly discriminated between individuals who went on to be frail at follow-up. We present the first evidence that immune-endocrine biomarkers are associated with the likelihood of frailty as well as mortality over a 10-year period. This augments our understanding of the aetiology of frailty, and suggests that a screening programme at ages 60–70 years could help to identify individuals who are at high risk of becoming frail and who would benefit from early, targeted intervention, for example with DHEA supplementation or anti-inflammatory strategies. Progress towards the prevention of frailty would bring major health and socio-economic benefits at the individual and the population level.

With aging, customary gait patterns change and energetic efficiency declines, but the relationship between these alterations is not well understood. If gait characteristics that develop with aging explain part of the decline in energetic efficiency that occur in most aging individuals, then efforts to modify these characteristics could delay or prevent mobility limitation. This study characterizes gait patterns in older persons with and without knee pain and tests the hypothesis that changes in gait characteristics due to knee pain are associated with increased energetic cost of walking in older adults. Study participants were 364 men and 170 women aged 60 to 96 years enrolled in the Baltimore Longitudinal Study of Aging (BLSA), of whom 86 had prevalent knee pain. Gait patterns were assessed at participant self-selected usual pace in the gait laboratory, and the energetic cost of walking was assessed by indirect calorimetry during self-selected usual pace walking over 2.5 min in a tiled corridor using a portable equipment. Participants with knee pain were less energetically efficient than those without pain (oxygen consumption 0.97 vs. 0.88 ml/(10 m · 100 kg); p = 0.002) and had slower gait speed and smaller range of motion (ROM) at the hip and knee joints (p < 0.05, for all). Slower gait speed and lower knee ROM in participants with knee pain and longer double support time and higher ankle ROM in participants without knee pain were associated with lower energetic efficiency (p < 0.05, for all). Slower gait speed and lower knee ROM were correlates of knee pain and were found to mediate the association between age and oxygen consumption. Although knee pain is associated with a higher energetic cost of walking, gait characteristics associated with energetic efficiency differ by pain status which suggests that compensatory strategies both in the presence and absence of pain may impact gait efficiency.