Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Centre of Postgraduate Medical Education, Warsaw
Prof. Monika Puzianowska-Kuźnicka, MD, researches the clinical and molecular aspects of extreme longevity and healthy aging, including the endocrinology of aging. Additionally, she is interested in molecular mechanisms of skin aging.
International Institute of Molecular and Cell Biology, Warsaw
Prof. Jacek Kuźnicki studies the molecular mechanisms occurring in neurodegenerative diseases including Alzheimer’s, Parkinson’s, and Huntington’s disease. He is also interested in calcium- and catenin-dependent signal transduction pathways in the brain.
Like most patho-physiological processes, the aging of the body starts at a molecular level. Until recently, aging was thought to be primarily caused by reactive oxygen species, which damage cellular molecules, particularly DNA. Recently, however, increased attention has been paid to other causes, including age-related changes in gene activity that occur as a result of epigenetic drift. Epigenetic modifications, namely genomic DNA methylation, modifications of DNA-associated histone proteins, and short non-coding RNA (microRNA) operation, affect the activity of the genes without altering their sequence. Although the epigenome remains stable, it can be modified in a subtle manner, primarily due to the impact of the environment. It can therefore be held that aging at a molecular level is not associated with the accumulation of alterations in gene sequence but is more an outcome of their malfunctioning, which is also affected by environmental conditions through epigenetic processes. Changes at the molecular level cause gradual deterioration in the way the cell functions, and, consequently, its senescence and death. As a result, the body gradually loses its ability to maintain homeostasis and there is a steadily increasing risk of development of aging-associated diseases, including type 2 diabetes, various types of cancer, neurodegenerative and cardiovascular diseases.
The rate and course of the aging process is influenced by a range of factors, which can be classified into three groups: genetic, non-genetic (mainly environmental), and random (see the figure above). Studies of monozygotic twins have shown that prior to the age of 90, the course of aging and longevity is only 20-25% dependent on gene variants inherited from one’s parents, with the main impact during this period being exerted by environmental factors. This theory has been corroborated by numerous observational, epidemiological, and interventional studies. People commonly attribute their poor health to “bad genes” yet in reality, family members often share a passion for unhealthy food and a lack of exercise, which, in turn, leads them to contract similar diseases. It is quite rare that a familial predisposition to a disease can actually be explained in terms of inherited genes.
The secret of centenarians
Genetic factors do become more important in the aging process after 90 years of age; their role becomes particularly significant in people who have reached the respectable age of 100. Numerous researchers – including our own teams – are working hard to unravel the molecular mechanisms that underlie successful aging, understood as enjoying a long and healthy life. Animal models have proven to be a rich source of information. They allow genetic manipulations to be carried out, involving the removal of a specific gene or its replacement with a mutated copy, as well as the performance of controlled environmental manipulation. The effect of such intervention on the phenotype of aging can be then observed. Humans, on the other hand, can be analyzed in terms of how specific polymorphic variants of genes correlate with the risk of disease or life span; comparative studies are also carried out for the entire genome.
Dozens of genes that are potentially involved in regulating the aging rate in humans have been revealed by scientific research. The most important of these genes are the APOE and TOMM40 genes, genes encoding components of the insulin pathway and insulin-like growth factor pathway, and FOXO transcription factor genes. Other genes under scrutiny are mTOR pathway genes, sirtuin genes, DNA repair protein-encoding genes, and deactivators of reactive oxygen species. Interestingly, the latest results of meta-analysis of whole-genome studies show that the genetic variants associated with longevity in Caucasians differ from those associated with longevity in Japanese. Perhaps, therefore, the genes that regulate the aging rate are not commonly shared by all ethnic groups and most of them could be specific to one particular race; this may be due to diverse environmental conditions (selective pressure). The research results published to date are far from conclusive and we are at the initial stages of understanding the genetic mechanisms regulating the aging rate in humans.
The source of eternal youth
So far, the most significant factor known to slow down the aging progress and mitigate its negative consequences is a healthy lifestyle. The appropriate diet is of particular importance, as it may affect the functioning of the genome through epigenetic processes (see the figure on the next page). Currently, it is believed that the most beneficial factor is a balanced calorie-restricted diet that fully covers the demand for micronutrients, vitamins, essential amino acids, etc., but also contains 20-30% less calories than the ad libitum diet. Recent research suggests that a caloric restriction of only 10-15% may also be effective in delaying the aging process; this assertion, however, requires further study. The composition of the diet is also of utmost importance. Healthy individuals, without any special dietary requirements, should adopt a diet based on unprocessed and low-processed plant foods (including vegetables, fruits, whole grains, nuts), combined with a small amount of vegetable oil and animal products, preferably fish and seafood. These recommendations are met by, for example, traditional Mediterranean diets, the advantages of which have been confirmed in numerous studies. A vegetarian diet is also favorable, providing that some elements (i.e., vitamin B12 and B6) are supplemented. On the other hand, unbalanced (deficient) diets are not recommended. The future of dietary prevention and treatment unquestionably lies in the designing of personalized diets based on one’s genome sequence. Other important factors delaying aging include moderate but regular physical activity and avoiding negative environmental factors including stimulants (e.g., tobacco, excessive intake of alcohol), overexposure to the sun, chemicals, etc.
For years, researchers have been striving to develop pharmaceuticals able to slow down the aging process. This is not an easy task, mainly due to the multitude of factors involved in regulating this process. High expectations are associated with pharmaceuticals such as metformin, rapamycin, and resveratrol, which may neutralize the negative impact of the environment at a molecular level. Thanks to them, the organism would function such as on a healthy, low-calorie diet, regardless of the actual composition of the meals. The journal Science, in turn, has recently published an article stating that the aging process in mice can be delayed/reversed through blood transfusion from younger individuals or by administering GDF11 factor. This factor has already been produced in its pure form, although the molecular mechanism of its action has yet to be understood. Thus, despite promising research results, we should not be expecting effective anti-aging pharmaceuticals anytime soon.
Sad face of old age
Aging of whole populations is becoming an increasingly worrying issue for developed countries. While on the one hand the limits of old age are being pushed ever-further and people stay active longer, the proportion of people suffering from chronic diseases, including neurodegenerative diseases like Alzheimer’s and Parkinson’s, is also surging. It is estimated that in Poland alone there are currently around 400,000 people experiencing dementia associated with Alzheimer’s disease, a figure that can only be expected to increase. Thanks to the progress of medicine, individuals suffering from these diseases are commonly in a relatively good physical condition, but require constant care and their disease may last for years, becoming a tragedy for themselves and their families.
In about 5% of the cases, Alzheimer’s disease is caused by an inherited mutation of one of the three genes encoding presenilin 1 or 2 or amyloid precursor protein (APP), which triggers the development of the disease early in life; sometimes as early as at 30 or 40 years of age. However, for the majority of the population, the main risk factor is age. Some studies suggest that the development of the disease can be delayed by a healthy diet, maintaining proper blood pressure and blood glucose level, physical activity and exercising the memory. Moreover, such actions make sense even if the early stages of dementia have already been diagnosed, as these factors slow down further development of the disease. Notably, it is strongly discouraged to isolate dementia patients, because social contacts have a significant therapeutic effect.
Exercise your brain!
Our studies conducted within the Polsenior project have discovered almost linear inverse relationship between the number of years of education and the risk of dementia. Moreover, better educated and creatively working individuals (scientists, teachers, musicians, etc.) were found to experience clinically evident effects of neurodegenerative disease later on in life than those working manually. Moreover, the progress of the disease may be slower because well educated individuals are better equipped to compensate for losses. For example, they struggle less to find a synonym for a forgotten word. Continuous mental activity is also important for maintaining a high level of cognitive skills during natural aging; such activity may include playing a musical instrument or learning a foreign language, even if started late in life.
Although age-related issues are usually first considered fairly late in life, the course of aging actually depends on our whole life. Moreover, some researchers argue that the health of parents prior to conception can significantly impact the health of their offspring late in life, and even the health status of the previous generations may also matter. Truly important factors, when considering the risk of aging-related diseases in offspring, seem to be the health of the mother, her diet and living environment during pregnancy (see Fig. above). This risk is primarily increased, however, by inappropriate behaviors after birth; the longer we are subjected to adverse environmental influences, the greater the risk that we will age faster and in an unfavorable manner. Therefore, children should be taught the principles of good nutrition and engage in regular physical activity from an early age. However, it is never too late to change bad habits. A healthy diet and an active lifestyle, even if they are introduced during retirement, will still yield positive results.
The ongoing advancement of science and medicine greatly helps all patients. It cannot, however, be forgotten that prevention is better than any cure. Therefore, regardless of the nature of molecular mechanism of aging, to mitigate its course, simple preventive measures must be taken. We ourselves are responsible for the quality of life we experience in our old age.
Factors affecting life expectancy
Interactions between food and genome. Diet influences the gene activity in a number of mechanisms, also through epigenetic modifications and direct impact on the activity of transcription factors. Dietary intake of specific components places selective pressure and promotes maintenance in the population of genetic variants, which encode proteins enabling their effective digestion and absorption.
Epigenetic programming hypothesis. Inappropriate environment at the stage of embryonic and fetal development can lead to subtle epigenome changes resulting in unfavorable modification in gene activity, changes in metabolism and increased risk of aging-related diseases. While the greatest reduction in these risks are achieved through early intervention, this intervention can be effectively implemented at any stage of life.
Further reading:Mossakowska M., Broczek K., Wieczorowska-Tobis K., Klich-Raczka A., Jonas M., Pawlik-Pachucka E., Safranow K., Kuznicki J., Puzianowska-Kuznicka M. (2014). Cognitive performance and functional status are the major factors predicting survival of centenarians in Poland. J Gerontol A Biol Sci Med Sci.; 69. 1269-1275.
Sebastiani P., Bae H., Sun F.X., Andersen S.L., Daw E.W., Malovini A., Kojima T., Hirose N., Schupf N., Puca A., Perls T.T (2013). Meta-analysis of gene-tic variants associated with human exceptional longevity. Aging (Albany NY); 5. 653-661.
© Academia 3 (43) 2014