Updates on Scientific Research of Longevity
Compiled by Kevin W Chen, Ph.D.
Exploring the role of genetic variability and lifestyle in oxidative stress response for healthy aging and longevity. Int J Mol Sci. 2013; 14(8):16443-72. By Dato S, Crocco P, D’Aquila P, et al. from University of Calabria, Italy. s.dato@unical.it — Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to have evolved conservative stress response mechanisms, probably derived from a combination of a diet rich in natural antioxidants, an active lifestyle and a favorable genetic background, particularly rich in genetic variants able to counteract the stress overload at the level of both nuclear and mitochondrial DNA. The integration of these factors could allow centenarians to maintain moderate levels of free radicals that exert beneficial signaling and modulator effects on cellular metabolism. Considering the hot debate on the efficacy of antioxidant supplementation in promoting healthy aging, in this review we gathered the existing information regarding genetic variability and lifestyle factors which potentially modulate the stress response at old age. Evidence reported here suggests that the integration of lifestyle factors (moderate physical activity and healthy nutrition) and genetic background could shift the balance in favor of the antioxidant cellular machinery by activating appropriate defense mechanisms in response to exceeding external and internal stress levels, and thus possibly achieving the prospect of living a longer life. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759920/ 
Epigenetic genome-wide association methylation in aging and longevity. Epigenomics. 2012 Oct;4(5):503-9. By Ben-Avraham D, Muzumdar RH, Atzmon G. — The aging phenotype is the result of a complex interaction between genetic, epigenetic and environmental factors. Evidence suggests that epigenetic changes (i.e., a set of reversible, heritable changes in gene function or other cell phenotype that occurs without a change in DNA sequence) may affect the aging process and may be one of the central mechanisms by which aging predisposes to many age-related diseases. The total number of altered methylation sites increases with increasing age, such that they could serve as marker for chronological age. This article systematically highlights the advances made in the field of epigenomics and their contribution to the understanding of the complex physiology of aging, lifespan and age-associated diseases. (For an introductory video on epigenetic and mind-body connection, please see https://www.youtube.com/watch?v=Y-Hh7b3Nxxc)
Exercise and longevity. Maturitas. 2012 Dec;73(4):312-7. By Gremeaux V, Gayda M, Lepers R, et al. from Cardiovascular Prevention and Rehabilitation Center (Centre ÉPIC), Montreal Heart Institute, Quebec, Canada. — Aging is a natural and complex physiological process influenced by many factors, some of which are modifiable. As the number of older individuals continues to increase, it is important to develop interventions that can be easily implemented and contribute to “successful aging.” In addition to a healthy diet and psychosocial well-being, the benefits of regular exercise on mortality, and the prevention and control of chronic disease affecting both life expectancy and quality of life are well established. We summarize the benefits of regular exercise on longevity, present the current knowledge regarding potential mechanisms, and outline the main recommendations. Exercise can partially reverse the effects of the aging process on physiological functions and preserve functional reserve in the elderly. Numerous studies have shown that maintaining a minimum quantity and quality of exercise decreases the risk of death, prevents the development of certain cancers, lowers the risk of osteoporosis and increases longevity. Training programs should include exercises aimed at improving cardiorespiratory fitness and muscle function, as well as flexibility and balance. Though the benefits of physical activity appear to be directly linked to the notion of training volume and intensity, further research is required in the elderly, in order to develop more precise recommendations, bearing in mind that the main aim is to foster long-term adherence to physical activity in this growing population. http://www.sciencedirect.com/science/article/pii/S0378512212003015
The role of exercise capacity in the health and longevity of centenarians. Maturitas. 2012; 73(2):115-20. By Venturelli M, Schena F, Richardson RS. From Dept of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Italy. massimo.venturelli@univr.it — Aging is a continuum of biological processes characterized by progressive adaptations which can be influenced by both genetic and physiological factors. In terms of human maturation, physically and cognitively functional centenarians certainly represent an impressive example of successful healthy aging. However, even in these unique individuals, with the passage of time, declining lung function and sarcopenia lead to a progressive fall in maximal strength, maximal oxygen uptake, and therefore reduced exercise capacity. The subsequent mobility limitation can initiate a viscous downward spiral of reduced physical function and health. Emerging literature has shed some light on this multi-factorial decline in function associated with aging and the positive role that exercise and physical capacity can play in the elderly. Recognizing the multiple factors that influence aging, the aim of this review is to highlight the recently elucidated limitations to physical function of the extremely old and therefore evaluate the role of exercise capacity in the health and longevity of centenarians. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618983/
Exploring age-related brain degeneration in meditation practitioners. Ann N Y Acad Sci. 2013 Aug 7. by Luders E. from Dept of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, Ca. — A growing body of research suggests that meditation practices are associated with substantial psychological as well as physiological benefits. In searching for the biological mechanisms underlying the beneficial impact of meditation, studies have revealed practice-induced alterations of neurotransmitters, brain activity, and cognitive abilities, just to name a few. These findings not only imply a close link between meditation and brain structure, but also suggest possible modulating effects of meditation on age-related brain atrophy. Given that normal aging is associated with significant loss of brain tissue, meditation-induced growth and/or preservation might manifest as a seemingly reduced brain age in meditators (i.e., cerebral measures characteristic of younger brains). Surprisingly, there are only three published studies that have addressed the question of whether meditation diminishes age-related brain degeneration. This paper reviews these three studies with respect to the brain attributes studied, the analytical strategies applied, and the findings revealed. The review concludes with an elaborate discussion on the significance of existing studies, implications and directions for future studies, as well as the overall relevance of this field of research. http://onlinelibrary.wiley.com/doi/10.1111/nyas.12217/abstract;jsessionid=65A62141CD6B1FFE3F79C58C709CE16E.f02t01
The search for longevity and healthy aging genes: insights from epidemiological studies and samples of long-lived individuals. J Gerontol A Biol Sci Med Sci. 2012; 67(5):470-9. By Murabito JM, Yuan R, Lunetta KL. From National Heart, Lung, and Blood Institute, Framingham, MA, USA. murabito@bu.edu — Genetic factors clearly contribute to exceptional longevity and healthy aging in humans, yet the identification of the underlying genes remains a challenge. Longevity is a complex phenotype with modest heritability. Age-related phenotypes with higher heritability may have greater success in gene discovery. Candidate gene and genome-wide association studies (GWAS) for longevity have had only limited success to date. The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium conducted a meta-analysis of GWAS data for longevity, defined as survival to age 90 years or older, that identified several interesting associations but none achieved genome-wide significance. A recent GWAS of longevity conducted in the Leiden Longevity Study identified the ApoE E4 isoform as deleterious to longevity that was confirmed in an independent GWAS of long-lived individuals of German descent. Notably, no other genetic loci for longevity have been identified in these GWAS. To examine the conserved genetic mechanisms between the mouse and humans for life span, we mapped the top Cohorts for Heart and Aging Research in Genomic Epidemiology GWAS associations for longevity to the mouse chromosomal map and noted that eight of the ten top human associations were located within a previously reported mouse life-span quantitative trait loci. This work suggests that the mouse and human may share mechanisms leading to aging and that the mouse model may help speed the understanding of how genes identified in humans affect the biology of aging. We expect these ongoing collaborations and the translational work with basic scientists to accelerate the identification of genes that delay aging and promote a healthy life span. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326242/
Genetics of healthy aging and longevity. Hum Genet. 2013 Aug 8. by Brooks-Wilson AR. From Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada, abrooks-wilson@bcgsc.ca. — Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analysis of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may ‘buffer’ the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.
Aging and longevity: why knowing the difference is important to nutrition research. Nutrients. 2011 Mar;3(3):274-82. By McDonald RB, Ruhe RC. From Dept of Nutrition, University of California, Davis, CA. rcruhe@ucdavis.edu — Life expectancies after the age of 70 and the number of individuals living with age-related chronic conditions that affect daily activities continue to increase. Age-specific nutritional recommendations may help to decrease the incidence or severity of age-related debilitating chronic disorders. However, research in this area has seen limited success in identifying nutrition-related mechanisms that underlie the functional loss and chronic conditions that occur as a function of time. We believe that the limited success in establishing age-specific nutrition recommendations for the older population reflects, at least in part, research designs that fail to consider the evolutionary and biological bases of aging and longevity. Longevity has evolved as a by-product of genes selected for their contribution in helping the organism survive to the age of reproduction. As such, the principle of genetic determinism provides an appropriate underlying theory for research designs evaluating nutritional factors involved with life span. Aging is not a product of evolution and reflects stochastic and/or random events that most likely begin during the early, reproductively-active years. The genetic determinism model by which young (normal, control) are compared to old (abnormal, experimental) groups will not be effective in identifying underlying mechanisms and nutritional factors that impact aging. The purpose of this commentary is to briefly discuss the difference between aging and longevity and why knowing the difference is important to nutrition research and to establishing the most precise nutritional recommendations possible for the older population. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257745/
Norm (front center) and his class at Friendship Village
Gender and the regulation of longevity: implications for autoimmunity. Autoimmun Rev. 2012; 11(6-7):A393-403. By Pan Z, Chang C. from Nemours/A.I duPont Hospital for children, Division of Allergy, Asthma and Immunology, USA. — For humans and other animals, gender has an influence not only on their physical attributes, but also on life span. In humans, females have a longer life span than males. The reasons for this are not entirely clear. The role of gender in the regulation of longevity may be linked to gender specific genetic differences, including the expression of sex hormone patterns and the changes in these patterns during an individual’s lifetime. In addition, the effect of sex hormones on other physiologic responses to environmental influences on cellular stress and oxidative damage may play a role in longevity. Gender can impact many disease states, including autoimmune diseases, and the factors that affect the development of autoimmune diseases and the regulation of longevity may share common mechanistic pathways. Other factors that may play a role include telomere and telomerase related differences, caloric restriction and changes in mitochondrial DNA. Inflammatory and regulatory pathways such as insulin/IGF signaling and Target of Rapamycin (TOR) signaling may also play a role in longevity and aging-related diseases such as Alzheimer’s. The role of gender differences in the regulation of these pathways or factors is not entirely clear. The role of X-chromosome inactivation in longevity has also yet to be fully elucidated. http://www.sciencedirect.com/science/article/pii/S1568997211003053
Genetic mechanisms of longevity responses to dietary restriction. [Article in Chinese] Yi Chuan. 2011 Nov;33(11):1153-8. Huang J, Yang Z. from Institute of Geriatrics, The 5th Medical College of Peking University, Beijing, China. 55hj55@163.com — Dietary restriction effectively extends lifespan in mammals and decreases the incidence and progression of many age-dependent diseases. To understand the genetic mechanisms that longevity responses to dietary restriction would have far-reaching impacts on future medical treatments to deal with the aging problems. Until recently, we knew nothing about these mechanisms in metazoans. Recent advances of the genetic bases of energy sensing and life control in yeast, invertebrates, and mammals have begun to settle the problem. More evidence indicates that the brain has a principal role in sensing dietary restriction and extending lifespan in metazoans. This paper reviews recently development of mechanisms, regulatory factors, genes, nervous control, and related hypothesizes of DR-longevity mechanisms in metazoans.
Vitamin D, sunlight and longevity. Minerva Endocrinol. 2011 Sep;36(3):257-66. by Pérez-López FR, Fernández-Alonso AM, Mannella P, Chedraui P. from Dept. of Obstetrics and Gynecology, University of Zaragoza, Zaragoza, Spain. faustino.perez@unizar.es — Humans acquire vitamin D through skin photosynthesis and digestive intake. Two hydroxylations are needed to obtain the bioactive compound, the first produces 25-hydroxyvitamin D [25(OH)D], and the second 1,25-dihydroxyvitamin D [1,25(OH)2D]. There is no consensus regarding the appropriate cut-off level to define the normal serum 25(OH)D range. Experimental, epidemiological and clinical studies have related low vitamin D status with longevity. Although some results are controversial, low serum 25(OH)D levels have been linked to all-cause, cardiovascular, cancer and infectious related mortality. Throughout life span a significant proportion of human beings display insufficient (20-30 ng/mL) or deficient (<20 ng/mL) serum 25(OH)D levels. Appropriate lifestyle changes, such as regular short exposures to sunlight (15 min a day), and an adequate diet that includes vitamin D rich components, are not always easily accomplished. Studies relating to vitamin D supplementation have methodological limitations or are based on relatively low doses. Therefore, dosages used for vitamin D supplementation should be higher than those traditionally suggested. In this sense, there is an urgent need for prospective controlled studies using high daily vitamin D doses (2,000 IU or higher) including cardiovascular, cancer, infectious and other endpoints. Relationship between vitamin D and health outcomes is not linear, and there are probably various optimal vitamin D levels influencing different endpoints. http://www.minervamedica.it/en/journals/minerva-endocrinologica/article.php?cod=R07Y2011N03A0257
Wisdom and method: extraordinary practices for the realization of longevity and optimal health. Ann N Y Acad Sci. 2009;1172:344-7. by Tsondu GN, Dodson-Lavelle B. from Tibet House, New York, New York, USA. — The focus in our discussion of longevity-enhancement has centered on developing techniques and technologies to control the environment as well as the physical body and its functions. The Tibetan contemplative and medical sciences offer a sophisticated view of the mind-body complex in which efforts to control the external world are insufficient without the development of “inner” technologies to train the mind. From the Tibetan perspective, training the mind is in fact essential to the realization of extraordinary levels of longevity, happiness, and optimal health.
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