Mechanisms that suppress the activities associated with cellular growth and proliferation, such as senescence and apoptosis, which fundamentally rely on the activities of tumor suppressor loci such as TP53 and INK4α/ARF also contribute to the deterioration in the reproductive...

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Aging is a biological process common to almost all eukaryotes. It is characterized by the declining ability to respond to stress, homeostatic imbalance and increased risk of disease. On the cellular level, the process of aging manifests itself in senescence, the permanent loss of ability to divide... >> MORE

Telomeres are structures composed of a specific DNA sequence and specialized proteins that cap the ends of chromosomes. Telomeres stabilize the chromosome, and thus ensure that the genome is maintained in a normal, stable state. Normal human cells lose a small amount of telomeric DNA each time...

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Progeroid syndromes are groups of diseases in which patients develop features of accelerated aging early in life. Two of the best-known progeroid syndromes are Hutchinson-Gilford progeroid syndrome (HGPS, ìProgeria of Childhoodî) and Werner syndrome (WS, ìProgeria of Adultsî). HGPS is a... >> MORE

Neurodegenerative diseases share many molecular and pathological similarities, yet no unifying explanation exists to explain how and why they arise. We propose that defects in a novel biological system underlie development of these disorders, and will test this hypothesis by investigating a...

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Aging is a complex process controlled by various genetic elements and environmental factors. It is characterized by a combination of deteriorative processes after a period of development of an organism. In mammals, extensive cell proliferation and tissue repair in adult organisms are required to... >> MORE

Germ cells can be passed from one generation to the next, indefinitely. Therefore, the germline has the potential to proliferate indefinitely and is an immortal cell lineage. In contrast, somatic cells are only needed for a single generation, and biological theory predicts that the germline may...

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My laboratory is interested in understanding the molecular mechanisms by which chromatin signaling networks effect epigenetic programs to influence aging-dependent processes. Our work centers on the biology of protein lysine methylation, a principal chromatin-regulatory mechanism thought to be... >> MORE

When normal human cells are removed from the body and cultured in a petri dish, they continue to divide only a limited number of times, after which they enter a state of dormancy known as replicative (or cellular) senescence. The induction of replicative senescence is caused by the erosion of DNA... >> MORE

The work leading up to the proposal for The Ellison Medical Foundation represents a novel paradigm for human aging and "premature aging" disorders in that it reverses the widely accepted notion that cell division creates two identical daughter cells. Cell division is the fundamental...

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Aging is characterized by a gradual functional decline of most organ systems. At the cellular level, virtually all somatic cells possess a limited proliferative lifespan after which they enter into a terminal growth arrest known as cellular senescence. Telomeres are specialized structures found at... >> MORE

Accurate segregation of chromosomes during mitosis is essential for maintenance of genomic integrity. Errors in this process cause an abnormal chromosome content, known as aneuploidy, which is a hallmark of most human cancers. To test whether aneuploidy is a cause or a consequence of the malignant... >> MORE

Cancers arise through the gradual acquisition of mutations in susceptible cells in the body - mutations that wreck the normal mechanisms that restrain cell growth, proliferation, survival movement and invasion and maintain normal architecture and dynamics of our tissue. There is an enormous...

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The major focus of my laboratory for the last 15 years has been on understanding the functions of a category of genes called tumor suppressors. As their name implies, a primary role of tumor suppressor genes is to prevent the onset of cancers. Cancers are often initiated when cells and their...

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It is well established that normal animal cells typically cannot divide in tissue culture indefinitely. Instead, cells that have completed a large number of divisions undergo replicative senescence, a process whereby the duplication of cellular chromosomal DNA comes to an end. The onset of...

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Epigenetics entails the study of the switching on and off of genes during development, cell proliferation and also by environmental insults. Epigenetic changes can result in the stable inheritance of a given spectrum of gene activities in specific cells. Genome modifications resulting from...

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Aging is accompanied and perhaps even defined by a gradual loss in the ability of the organism to respond successfully to fluctuations in the environment and maintain homeostasis. We have discovered that altered activity of the tumor suppressor p53 accelerates this process in the mouse. The...

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Normal cells grown in culture have a limited potential to divide and eventually become terminally non-dividing. This is called cell or replicative senescence and is used as a model to study aging at the cell level. Tumor-derived cells, in contrast, divide constantly without control. We have...

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Adult Drosophila tissues are post-mitotic except for the gonads, which contain both somatic stem cells and germ line stem cells. Oogenesis declines dramatically during aging, however it is unknown whether this results from a limited replicative potential of the stem cells or from other factors.... >> MORE

The overall aim of this grant is to provide new methods for the study of gene action in human aging, using cell transplantation techniques applied to human adrenocortical cells. Prior to beginning this grant, we had established methods for genetic modification of bovine adrenocortical cells and...

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The yeast Saccharomyces cerevisiae has become recognized as a model system for studying replicative senescence in eukaryotes. It permits easy genetic and physiological manipulations of cells, and a chance to examine aging cells in a homogeneous population. However, current methods of...

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The accumulation of deleterious mutations that act late in life is thought to play a pivotal role in the process of aging. In the genome, a likely repository for such mutations is the heterochromatin, which contains many repetitive elements but few actual genes. The objective of this project is... >> MORE

Previous studies have observed greater variation in gene expression in cells from older animals. This suggests that stochasticity in expression could be a cause of aging. We hypothesize that random, stochastic fluctuations in global gene expression can contribute to aging. To test our hypothesis,... >> MORE

Chromatin, the complex of DNA and associated proteins, is the physiological form of our genome. Chromatin is a dynamic template governed by intricate regulation, the mechanisms of which are just beginning to unfold. The basic fundamental repeating unit of chromatin is the nucleosome, which consists... >> MORE

The key physiological characteristic of aging is a failure to maintain tissue integrity due to progressive deterioration, coupled to the apparent exhaustion of normal regenerative potential. This may be due to environmental factors, such as DNA damage, which eventually cannot be overcome, and/or... >> MORE

Cellular senescence is a state in which cells permanently stop dividing. It occurs in response to cellular stresses, including DNA damage, and also due to shortening of chromosome ends (telomeres) caused by multiple rounds of cell division. Although senescence is believed to protect organisms... >> MORE

The human body is marked by interactions among individual cells, especially between neighboring cells. In young and healthy tissue, neighboring cells modify their internal structure and adhere to each other. This often leads to a collective change of cell morphology. Cell morphological change... >> MORE

γ-Secretase has long been regarded as an attractive anti-amyloid therapeutic target for Alzheimer's disease (AD). However, our studies demonstrated that mice with reduced levels of γ-secretase activity (Nct^+/- mice and Nct^+/-;PS1^+/-...

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Eastern grey squirrel is one of the longest-lived rodents. Its maximum documented lifespan is 23 years, which is almost 10 times longer than that of a mouse. Since squirrel is related to classical short-lived laboratory rodents such as mouse and rat, squirrel is an ideal model organism to... >> MORE

Our lab studies the basic mechanisms of transcriptional regulationówhat turns gene expression ìon or offî in human cells. A major aspect of our work involves a protein known as p53, which works primarily by triggering changes in gene expression patterns in response to specific cellular cues. Many... >> MORE

To understand the complex processes underlying human aging, the study of cellular "senescence" may recapitulate some aspects. Senescence is a cell fate program that can be triggered by environmental stimuli and stress. We have recently discovered that the major stress-inducible transcription...

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Expression of the tumor suppressor, p^16INK4a, increases with age. While this protein prevents cancer in many tissues by inducing senescence, p^16INK4a appears also to contribute to aging. To elucidate the links between aging and senescence, we will evaluate p^16INK4a... >> MORE

The main focus of our laboratory is to understand the biological bases of association between poly(ADP-ribosyl)ation and an organism development and longevity. Protein poly(ADP-ribosyl)ation (pADPr) levels are determined by the relative activity of poly(ADP-ribose) polymerase (PARP) and tankyrase... >> MORE

In vitro cellular senescence, since its first description in the literature, has been put forward as a model for aging in species with mitotically active tissues. Evidence suggests that sub-lethal levels of DNA damage, including telomere loss, induce the cellular senescence phenotype in normal... >> MORE

The adapter protein Shc, which couples mitogenic signals from cell surface receptors through the Ras/MAPK pathway, has recently been implicated as a determinant of mammalian longevity, as mice harboring a targeted knockout of p66^shc live 30% longer than control littermates. In...

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The majority of patients with cancer in the United States are more than 70 years old and cancer has been regarded as a disease of aging. Aging-related decline of the immune response has also been well documented. Our long-term goals are to identify molecular targets for drug development...

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One major advance in the study of mammalian aging was the discovery made by Hayflick in the 1960's. He observed that normal human cells had a finite lifespan in vitro and could execute only a limited number of cell divisions. Beyond this limit, cells undergo an irreversible growth arrest...

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Chromosomes, the carriers of the cell's genetic information, are composed of distinct functional domains that ensure their fateful inheritance during the process of cell division and chromosome duplication. One example of such functional organization is the presence of large stretches of DNA... >> MORE

One intriguing puzzle in modern biology is how different life-spans and aging rates are determined in different species. Answers to such questions will help us battle various aging-related diseases, and ultimately improve the health and quality of life in humans. Aging rates are believed to be... >> MORE