Life Extension Magazine

Life Extension Magazine July 2006

Report

Longevity Genes and Caloric restriction

By Xi Zhao-Wilson, PhD, and Paul C. Watkins, SM, of BioMarker Pharmaceuticals

By Xi Zhao-Wilson, PhD, and Paul C. Watkins

Groundbreaking research funded by the Life Extension Foundation and conducted at BioMarker Pharmaceuticals in northern California is unraveling the factors responsible for aging and disease, as well as strategies and technologies that may one day help us live in good health for more than 100 years.

In this article, we discuss dramatic breakthroughs in life-extension technologies such as gene expression and caloric restriction, along with steps you can begin taking today to ensure a long and disease-free life.

The year is 1890 and you have just been born. You are expected to live a long, full life, raise a family, pursue a career, and leave a legacy behind before you die at the ripe old age of 45. That was the average life expectancy of Americans born at the close of nineteenth century, who thought they were living a natural, productive, and full life span.

Today, based on 2006 estimates in the World Factbook, Brazilians will live to be 71.97 years old on average, Americans will live to be 77.85 years old, Canadians will live to 80.22 years, and Japanese to 81.25 years.1 Life expectancy in the most developed nations is expected to slowly increase and peak in the mid-80s, while some visionaries foresee an eventual life span of hundreds of years or longer. Like our ancestors of the late 1800s, many people today still believe that life expectancy can be predicted solely by looking at the current actuarial data, and that there really is not much we can do to change it.

What controls the rate at which we age, and which factors determine the potential maximum human life span? Biogerontologists are actively addressing these questions, using the most recent advances in science and technology. The Life Extension Foundation has played a significant role in funding and promoting biomedical aging research. By contrast, the National Institutes of Health invests less than 0.1% of its annual budget—which totaled $28 billion in 2006—in research on the biology of aging and its relation to age-related diseases.

Recent developments in genetics, genomics, and biogerontology are providing clues as to which factors in our genes, diet, and environment determine how long we can live. These inquiries seek to understand how we can live longer and also improve the quality of our lives by removing the burden of chronic diseases associated with growing older.

Longevity Genes in Yeast, Worms, Flies, and Mice

Scientists studying the genetic basis of aging know that certain genes—especially in scientific models such as yeast, worms, and flies—can have a profound influence on the maximum life span of those organisms. Interest is now shifting to the search for similar genes in higher organisms such as mice, which serve as a valuable pre-clinical animal model for drug-discovery research in humans.

The number of genes that have been found to influence aging in model organisms is expanding, as shown in Table 1.2 The goal of scientists searching for longevity genes is to understand how these genes function, the roles they play within specific molecular pathways, how they control fundamental biological processes, and to what extent they or their functions are shared among different organisms. The key longevity genes, however, are those that provide information about why some species live longer than others, shedding light on factors that affect actual rates of aging. While scientists are just beginning to identify these genes, they believe that such genes are responsible for regulating complex developmental and degenerative processes, and that further study will provide clues for both life-span extension and chronic disease prevention.

The longevity genes so far identified in yeast, flies, worms, and mice are under intensive study to determine their biological functions and how these functions relate to extending life span. Important insights are emerging. For example, several genes that are shared among these very different species appear to function in the insulin-signaling pathway, offering a clue to the relationship between life span and the regulation of metabolism. Other genes appear to be related to caloric restriction, which has radically extended life span in mammals. Understanding the mechanisms that link fewer total calories with life-span extension is of central importance, and is an area that strongly interests the Life Extension Foundation.

Longevity Genes Found in Yeast, Worms, Flies, and Mice

Gene

Organism

Biological Function or Pathway

Age-1/Daf-23

Worm

PI-3 kinase, insulin-like signaling

Amp-1/AMPK

Worm

Activated protein kinase, metabolism and stress response, metformin enhances AMPK levels

Chico

Fly

Insulin-like signaling—second step in pathway

Clk-1

Worm

Mitochondrial polypeptide similar to yeast CoQ7, clock genes

Ctl-1

Worm

Catalase

Daf-2

Worm

Insulin-like signaling, IGF-1-like receptor

Daf-16

Worm

Transcription factor, stress resistance

Eat-2

Worm

Unknown

Ghr

Mouse

Growth hormone receptor

Ghrhr

Mouse

Growth-hormone-releasing hormone receptor

Hsp70

Fly

Heat shock protein

Indy

Fly

Dicarboxylic acid transport protein

InR

Fly

Insulin/IGF-1-like receptor

Klotho

Mouse

Membrane protein with ß-glucosidase activity, insulin, IGF-1 and vitamin D regulation

Methuselah/CD97

Fly

Stress resistance and nerve cell communication

MsrA

Mouse

Methionine sulfoxide reductase

Mth

Fly

Transmembrane protein, stress resistance

Old-1/old-2

Worm

Receptor tyrosine kinases, stress resistance

P53

Mouse

Tumor suppressor protein

P66shc

Mouse

Free radical production

Pcmt

Fly

Protein carboxyl methyltransferase

Pit1/Prop1

Mouse

Pituitary activity, dwarfism

SIR2/SIRT1

Yeast, worm, fly

NAD+ dependent histone deacetylase, cell survival, metabolism, stress responses

Sod-1

Fly

Cu/Zn-superoxide dismutase, oxidative stress

Sod-2

Mouse

Mn-superoxide dismutase, oxidative stress

TOR

Yeast, worm, fly

PIK-related protein kinase and rapamycin target, nutrient sensor

Upa

Mouse

Urokinase-type plasminogen activator

Yeast: baker's yeast (Saccharomyces cerevisiae); worm: roundworm (nematode) (Caenorhabditis elegans); fly: fruit fly (Drosophila melanogaster); mouse: house mouse (Mus musculus).

Uncovering Longevity Genes in Humans

While scientists cannot yet manipulate longevity genes in humans in the same ways they can in animals, several investigational approaches are under way to identify and understand the roles of these genes in humans.

One approach involves the study of families that exhibit exceptional longevity. These investigations have shown that the offspring of centenarians (people who live to 100 years or older) are likely to inherit significantly better health, as measured by the prevalence of hypertension, diabetes, heart attack, and stroke.3 Longevity in these individuals appears to be highly correlated with relatively high levels of beneficial high-density lipoprotein (HDL) and low levels of harmful low-density lipoprotein (LDL), as well as with larger molecule sizes of both HDL and LDL. Those individuals who inherit a specific polymorphism (a variation of a certain gene) enjoy exceptional longevity, in addition to much better health and cognitive performance.4

This is the first example of linking a human gene mutation to an exceptional longevity phenotype (the characteristics of an organism, as determined by both genetic and environmental influences). The mutation in this case is in a gene involved in lipoprotein metabolism, known as CETP (cholesteryl ester transfer protein, plasma). It suggests that other such genes are likely to be discovered through similar studies of families. This kind of research is helping to identify which genotype (the genetic make-up of an organism) can lead to extended disease-free aging.

The same research group recently identified another longevity-linked gene associated with lipoprotein levels and sizes. A polymorphism for the gene apolipo-protein C-III, or APOC3, is linked to a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity.5 Just how many such genes influence longevity and how they contribute to your health and chances for a long life span remain unanswered questions.

Aside from the genetic advantages with which some of us are born, the real question is: are there genes we all share that could be manipulated to help us live longer and healthier? For an answer to this question, we begin our inquiry at the level of the single-celled organism that makes bread dough rise.

A Little Stress May Be a Good Thing

In the mid-1990s, a professor at the Massachusetts Institute of Technology discovered that a single gene in yeast, when present in multiple copies, caused the life span of the mother yeast cell to increase by about 30%. Life span in yeast can be measured by counting the number of times a mother cell divides to produce daughter cells before dying. This story grew more compelling when it was found that this gene “codes” for an enzyme that works directly on proteins surrounding DNA, and that extra copies of this gene, known as SIR2, also extended the life span of worms (the nematode C. elegans) by as much as 50%. The SIR2 gene and its mammalian homologue, SIRT1, are now the focus of intensive study regarding their connections and functions in relation to how organisms respond to stress.

MIT professor Leonard Guarente and his former post-doctoral fellow, David Sinclair, who is now at Harvard University, recently coauthored an article in Scientific American that describes the interesting history behind the SIR2/SIRT1 story.6 It turns out that the gene relatives of SIR2, called sirtuins, have evolved to connect genetics with aging, diet, and environmental stressors. These scientists now believe that genes involved in an organism’s ability to withstand a stressful environment can boost the body’s natural capacity to ward off the decline normally associated with aging. The organism’s response seems to be an increase in its capability for defense and repair. In essence, so-called longevity genes like SIR2 are survival genes, in that they enhance health status and extend life span.

Mild stressors, such as caloric restriction, can activate the sirtuin pathways. The result is a coordinated shift in an organism’s metabolism, including improved DNA stability, increased repair of DNA damage, improved immune function, prolonged cell survival, and enhanced energy production.

Life-Extending Benefits of Resveratrol

A key finding that further elevates this story to potential relevance for humans is the discovery that certain molecules, called sirtuin activators, can “turn on” this pathway. One of these molecules, resveratrol, is found in red wine and grape extracts. Various plants produce resveratrol in response to stress. Resveratrol drew particular attention when scientists found that resveratrol-fed flies and worms both exhibited significant increases in life span. Survival studies of mice are currently under way, since the biological mechanisms that respond to compounds like resveratrol are believed to be conserved in mice as well as in humans.

In addition to its effects on aging, resveratrol has also been effective in animal models of neurological disease. Resveratrol protects against cell death in worm and mouse models of Huntington’s disease, and protects against amyloid beta toxicity, which suggests a therapeutic potential for resveratrol and other sirtuin-activating compounds in Alzheimer’s disease.7,8

Recent studies funded by the Life Extension Foundation and conducted by BioMarker Pharmaceuticals in northern California have showed significant beneficial effects of grape extract with resveratrol. The biological consequences of increased life span and improvement of neurological disorders in an animal model have been dissected at the molecular level. Further investigations into the links between specific genes and cellular pathways are under way.

Resveratrol and other sirtuin activators may be no more than a chapter in the book of longevity, but the rest of the story will require a greater understanding of all the molecular pathways, critical gene targets, and suitable intervention points necessary to manipulate something as complex as the mechanisms that control the rate at which we age. We at BioMarker Pharmaceuticals are also attempting to moderate the risk of acquiring a host of chronic diseases associated with the aging process. Our emphasis is on preventing illnesses associated with aging, not just treating diseases once they arise.