Lecture Summaries

1 Introduction and course overview During our first meeting, we will spend some time introducing both the instructors and the students. Then, the instructors will present a general overview of the course, discuss the format, and explain the preparation that will be expected of each student each week. We will also begin to delve into the course material with an introduction to the theories that have been put forth to explain why and how aging occurs.
2 Introduction to calorie restriction Caloric restriction (CR) is the most robust and reproducible intervention known to extend lifespan. A reduction in caloric intake that maintains adequate amounts of nutrients reliably increases average and maximal longevity in organisms ranging in complexity from yeast to mammals. CR not only extends lifespan, it also delays the onset of age-related phenotypes in every model tested, making it a gold standard for slowing aging. Although it has been known for almost 80 years that CR extends lifespan in mammals, the mechanism underlying this effect still remains largely unknown. Today, we will discuss studies of CR in mammals, including a recent paper that demonstrates for the first time the lifespan-extending benefit of CR extends to a non-human primate, the rhesus monkey.
3 Cellular senescence and telomerase Since the 1960s it has been known that normal human cells can undergo only a finite number of cell divisions in culture. After that number of divisions has been reached, the cells stop dividing and take on an altered morphology, thereby entering a state known as senescence. It is now known that a major determinant of the number of cell divisions is the length of telomeres, the protective DNA caps at the ends of chromosomes. Because most human cells lack telomerase, the enzyme needed to maintain telomere length during replication, the telomeres shorten with every cycle of DNA replication and cell division until they become critically short, at which point the cells senesce. The importance of this phenomenon of "cellular aging" to aging at the level of the entire organism has been the subject of ongoing debate. It seems that for populations of cells that undergo many cell divisions in the adult animal, such as skin cells, telomeres do contribute to symptoms of aging over time, but telomeres may be less important in non-dividing cells, such as neurons.
4 Premature aging syndromes One way to gain insight into the molecular mechanisms underlying aging is to study organisms in which the rate of aging has been accelerated. This week we will study two examples of mice that age more rapidly than normal and thus resemble some very rare human premature-aging syndromes known as progeroid syndromes. First, we will learn about the chance discovery of a mouse gene that when mutated leads to an early aging phenotype. Next, we will explore the role of mitochondria in aging by seeing what happens in mice in which mitochondrial DNA accrues many more mutations than normal.
5 Lifespan extension in model organisms For almost 20 years, it has been known that single-gene mutations can extend the lifespan and delay the aging of an organism. Since the discovery of the first long-lived mutants, the use of genetics as a tool for aging research has rapidly expanded our understanding of the aging process. Because many important genes and pathways are conserved from yeast to humans, insights gained from simple organisms such as yeast, the roundworm C. elegans, and the fruit fly Drosophila may well shed light on aging pathways that are also important in humans. This week we will learn about genes in yeast and in the roundworm C. elegans that regulate lifespan.
6 Sirtuins in lifespan extension Sirtuins are a family of NAD+-dependent lysine deacetylases that are linked to metabolism and aging. Last week we discussed the first paper demonstrating a relationship between the yeast sirtuin protein SIR4 and longevity. Since this discovery, much work has been done to determine how sirtuin genes function in aging and whether they are conserved from simple organisms to more complex organisms. This week we will discuss how different sirtuin family members regulate lifespan extension in yeast by using distinct mechanisms. In addition, we will discuss the findings of a recent paper that describes the role of a mammalian homolog of sirtuins in aging.
7 Tor in model organisms The TOR (target of rapamycin) signaling pathway is an evolutionarily conserved signaling pathway through which organisms as diverse as yeast and humans regulate cell growth and protein translation in response to the availability of nutrients. We will discuss genetic screens of yeast and roundworms that have found that the TOR signaling pathway regulates lifespan, and discuss how these findings link the regulation of protein translation to aging.
8 Field trip to Boston Data Aging Club meeting at Harvard Medical School  
9 Oxidative stress theory of aging One of the most popular theories of aging postulates that the accumulation of oxidative damage to important macromolecules is a major cause of the cellular dysfunction seen with increasing age. Reactive oxygen species (ROS) are an unavoidable by-product of mitochondrial respiration. If not detoxified by anti-oxidant enzymes, ROS can react with proteins, lipids, and DNA and inflict significant damage. If left unrepaired, this damage can lead to declines in cellular function and viability. To explore the importance of oxidative damage in aging and the regulation of lifespan, we will first learn about the naked mole rat, a rodent the size of a mouse that can live for almost 30 years (ten times longer than a mouse). We will see how the accumulation of oxidative damage in this long-lived animal differs from that seen in the mouse. Next, we will learn about the effects of increasing the expression level of an important anti-oxidant enzyme in the mouse and the effect of these manipulations on lifespan.
10 Oxidative stress and aging: Beneficial effects Reactive oxygen species (ROS) are generally thought to be harmful and thus promote aging, and as we learned last week, decreasing the levels of ROS mediated damage can extend lifespan. Recently, an underappreciated role of ROS as a signaling molecule has become a topic for scientific investigation. This has led to the idea that low levels of ROS are not damaging and do not promote aging. Instead they initiate transcriptional programs in times of stress, allowing for adaptation and increased lifespan. The exact mechanism for this increased lifespan is not fully understood. This week we will discuss two papers that propose possible mechanisms behind this paradoxical increase in lifespan in the presence of increased ROS.
11 Reversing aging with drugs; activating sirtuins with resveratrol The discovery of genetic pathways that influence aging has added fuel to the quest for the fountain of youth through pharmacological interventions that target these pathways. Increased maximal lifespan of humans would have detrimental effects on our resources, but by increasing healthspan we could decrease the utilization of resources needed to treat the sick and at the same time increase the quality of life of the elderly. This week we will discuss a paper describing the naturally occurring compound resveratrol, which is found in red grapes and is thought to be an activator of sirtuins. Administration of this compound to rodents on a high-fat diet increases their health span and lifespan. The second paper discusses the same compound but demonstrates the necessity of a different pathway for its function.
12 Student oral presentations  
13 Reversing aging with drugs; inhibiting the TOR pathway with rapamycin During Week #7, we discussed how the TOR (target of rapamycin) signaling pathway regulates aging in yeast and C. elegans. This week, we will discuss the difficulties of screening for compounds that regulate aging in mice, and the rationale for the National Institute on Aging Interventions Testing Program. We will discuss recent findings that rapamycin, an FDA-approved compound, extends lifespan in mice, while resveratrol does not extend lifespan of mice when fed a normal chow diet. The second paper discusses the beneficial effects of rapamycin on the aging associated neurodegenerative condition, Alzheimer's disease.