MIT OPEN COURSEWARE: The Biology of Aging: Age-Related Diseases and Interventions

As taught in: Fall 2011

Shown above are 23 pairs of human chromosomes, with telomeres (protective DNA caps at the ends of the chromosomes) marked in white. In most human cells, telomeres become shorter with each cycle of DNA replication and cell division. The importance of telomere shortening to the process of cellular aging has been widely studied and debated. (Image by Hesed Padilla-Nash and Thomas Ried, the National Cancer Institute)

Instructors:

Dr. Dudley W. Lamming
Dr. Eric L. Bell

MIT Course Number:

7.342

Level:

Undergraduate

Course Description

Aging involves an intrinsic and progressive decline in function that eventually will affect us all. While everyone is familiar with aging, many basic questions about aging are mysterious. Why are older people more likely to experience diseases like cancer, stroke, and neurodegenerative disorders? What changes happen at the molecular and cellular levels to cause the changes that we associate with old age? Is aging itself a disease, and can we successfully intervene in the aging process?
This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.

Syllabus

Course Meeting Times

Lectures: 1 session / week, 2 hours / session

Prerequisites

Recommended prerequisites are:
7.03 Genetics
7.05 General Biochemistry
7.06 Cell Biology
7.28 Molecular Biology

Course Description

Aging involves an intrinsic and progressive decline in function that eventually will affect us all. While everyone is familiar with aging, many basic questions about aging are mysterious. Why are older people more likely to experience diseases like cancer, stroke, and neurodegenerative disorders? What changes happen at the molecular and cellular levels to cause the changes that we associate with old age? Is aging itself a disease, and can we successfully intervene in the aging process?
In this course, we will explore the scientific discoveries made from studies of model organisms, including yeast, worms, flies and mice, which have led to revelations about the molecular biology of aging. We will discuss calorie restriction, an intervention that extends the lifespan of organisms as diverse as yeast and primates, and the implications for successfully intervening in age-related diseases. We will also discuss the first tests of drugs such as resveratrol (a small molecule found in red wine) and rapamycin, which may target aging pathways in mammals. We will participate in a field trip to a meeting of the Boston Area Aging Data Club, where we will meet the authors of some of the papers that we have covered in class and hear a presentation by a researcher actively working on a hot topic in the field of aging.

Format

This course will meet weekly for two hours, during which we will discuss primary research papers from the scientific literature. Students will be required to read two papers each week and come to class prepared to discuss them.

Grading

This course is graded pass/fail. Successful conclusion of the course requires the completion of two assignments and regular participation in the weekly meetings.

Calendar

Course calendar.

WEEK #	TOPICS	KEY DATES
1	Introduction and course overview
2	Introduction to calorie restriction
3	Cellular senescence and telomerase
4	Premature aging syndromes
5	Lifespan extension in model organisms
6	Sirtuins in lifespan extension
7	Tor in model organisms	Written Assignment due (for students choosing papers from Week #7)
8	Field trip to Boston Data Aging Club meeting at Harvard Medical School
9	Oxidative stress theory of aging	Written Assignment due (for students choosing papers from Week #9)
10	Oxidative stress and aging: Beneficial effects
11	Reversing aging with drugs; activating sirtuins with resveratrol
12	Student oral presentations	Student oral presentations
13	Reversing aging with drugs; inhibiting the TOR pathway with rapamycin

 

Lecture Summaries

Lecture summaries.

WEEK #	TOPICS	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.

Readings

Course readings.

WEEK #	TOPICS	READINGS
1	Introduction and course overview See the Lecture Summary	No Readings
2	Introduction to calorie restriction See the Lecture Summary	Weindruch, R., R. L. Walford, et al. "The Retardation of Aging in Mice by Dietary Restriction: Longevity, Cancer, Immunity and Lifetime Energy Intake." Journal of Nutrition 116 (1986): 641-54. Colman, R. J., R. M. Anderson, et al. "Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys." Science 325 (2009): 201-4.
3	Cellular senescence and telomerase See the Lecture Summary	Allsopp, R. C., H. Vaziri, et al. "Telomere Length Predicts Replicative Capacity of Human Fibroblasts." Proc Natl Acad Sci 89 (1992): 10114-18. (PDF - 1.4MB) Rudolph, K. L., S. Chang, et al. "Longevity, Stress Response, and Cancer in Aging Telomerase-deficient Mice." Cell 96 (1999): 701-12.
4	Premature aging syndromes See the Lecture Summary	Varga, R., M. Eriksson, et al. "Progressive Vascular Smooth Muscle Cell Defects in a Mouse Model of Hutchinson-Gilford Progeria Syndrome." Proc Natl Acad Sci 103 (2006): 3250-5. (PDF - 2.7MB) Kujoth, G. C., A. Hiona, et al. "Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging." Science 309 (2005): 481-4.
5	Lifespan extension in model organisms See the Lecture Summary	Kennedy, B. K., N. R. Austriaco Jr., et al. "Mutation in the Silencing Gene SIR4 Can Delay Aging in S. cerevisiae." Cell 80 (1995): 485-96. Ayyadevara, S., C. Tazearslan, et al. "Caenorhabditis elegans PI3K Mutants Reveal Novel Genes Underlying Exceptional Stress Resistance and Lifespan." Aging Cell 8 (2009): 706-25.
6	Sirtuins in lifespan extension See the Lecture Summary	Kaeberlein, M., McVey M., et al. "The SIR2/3/4 Complex and SIR2 alone Promote Longevity in Saccharomyces cerevisiae by Two Different Mechanisms." Genes Dev 13 (1999): 2570-80. Herranz, D., M. Muñoz-Martin, et al. "Sirt1 Improves Healthy Ageing and Protects from Metabolic Syndrome-associated Cancer." Nature Communnication 1 (2010): 1-8.
7	Tor in model organisms See the Lecture Summary	Steffen, K. K., V. L. MacKay, et al. "Yeast Life Span Extension by Depletion of 60s Ribosomal Subunits is Mediated by Gcn4." Cell 133 (2008): 292-302. Hansen, M., S. Taubert, et al. "Lifespan Extension by Conditions that Inhibit Translation in Caenorhabditis elegans." Aging Cell 6 (2007): 95-110.
8	Field trip to Boston Data Aging Club meeting at Harvard Medical School	No Readings
9	Oxidative stress theory of aging See the Lecture Summary	Pérez, V. I., R. Buffenstein, et al. "Protein Stability and Resistance to Oxidative Stress are Determinants of Longevity in the Longest-living Rodent, the Naked Mole-rat." Proc Natl Acad Sci 106 (2009): 3059-64. (PDF) Schriner, S. E., N. J. Linford, et al. "Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria." Science 308 (2005): 1909-11.
10	Oxidative stress and aging: beneficial effects See the Lecture Summary	Schulz, T. J., K. Zarse, et al. "Glucose Restriction Extends C. elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress." Cell Metab 6 (2007): 280-93. Lee, S-J, A. B. Hwang, et al. "Inhibition of Respiration Extends C. elegans Life Span via Reactive Oxygen Species that Increase HIF-1 Activity." Current Biology 20 (2010): 2131-36.
11	Reversing aging with drugs; activating sirtuins with resveratrol See the Lecture Summary	Baur, J. A., K. J. Pearson, et al. "Resveratrol Improves Health and Survival of Mice on a High-calorie Diet." Nature 444 (2006): 337-42. Um, J-H, S-J Park, et al. "AMP-Activated Protein Kinase-Deficient Mice are Resistant to the Metabolic Effects of Resveratrol." Diabetes 59 (2010): 554-63. (PDF)
12	Student oral presentations	No Readings
13	Reversing aging with drugs; inhibiting the TOR pathway with rapamycin See the Lecture Summary	Miller, R. A., D. E. Harrison, et al. "Rapamycin, but not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice." J Gerontol A Biol Sci Med Sci 66 (2011): 191-201. Spilman, P., N. Podlutskaya, et al. "Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-βeta Levels in a Mouse Model of Alzheimer's Disease." PLoS One 5 (2010): e9979.

 

Assignments

Written Assignment (Due Week #7 or Week #9, Student's Choice)

Students will choose one of the two papers from either Week #7 or Week #9, and will write a brief (two page) analysis, due at the beginning of class for that same week. In this assignment, students will be expected to describe the questions that the authors wanted to answer, analyze the experiments that addressed these questions (focusing on the key experiments and controls), and provide a critique of the authors' interpretations of their results.

Oral Presentation (Due Week #12)

Students will prepare an oral presentation about a paper of their choice. Students will be expected to identify a topic of interest from the course, perform a literature search to identify more papers about the topic, and select one of these (subject to approval of the instructors) to be the subject of their presentations. Each student will be expected to present his or her selected paper to the class in approximately 15-20 minutes and address the same questions outlined above for the written assignment.

 

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Lamming, Dudley W., and Eric L. Bell. 7.342 The Biology of Aging: Age-Related Diseases and Interventions, Fall 2011. (Massachusetts Institute of Technology: MIT OpenCourseWare), http://ocw.mit.edu/ (Accessed 04 Jan, 2012). License: Creative Commons BY-NC-SA

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