What causes aging and age-related diseases, especially obesity, diabetes, and Alzheimer's disease?
The metabolic mystery: obesity and diabetes (a surfeit of nutritional resources) accelerate many age-related diseases, and dietary restriction (a dearthof nutritional resources) slows down aging itself and almost all age-related diseases. What's up with that?
Can we develop a drug to mimic all the protective effects of dietary restriction? (Yes!)
Our laboratory uses histological, behavioral, electrophysiological, and molecular, methods (including DNA microarrays and RNA interference) to assess the basic mechanisms by which hypothalamic neurons sense and regulate metabolic state (including body weight and food intake), and how these mechanisms are impaired in metabolic diseases and during aging. A driving question of our laboratory is what may be called the metabolic mystery. This refers to the fascinating phenomenon that obesity is a risk factor for most age-related diseases and indeed for mortality, and conversely dietary restriction appears to slow down the aging process and extend maximum lifespan. Considering that almost all major pathologies are influenced by caloric intake, the mechanisms underlying the metabolic mystery may be considered among the most compelling in biomedical science. We really don't understand why caloric intake should lead to diseases, but many lines of evidence suggest neuroendocrine mechanisms. We have begun to study the nature of the hypothalamic neurons which are sensitive to nutrition and which in turn regulate metabolic state, and we have thus begun to define a "nutritional field" of neurons which contain overlapping domains sensitive to different nutrients and which regulate different aspects of metabolism. Of particular interest is that the maximum overlap of these nutritional stimulation (e.g., glucose and leptin) may occur within the POMC neurons, which we now believe play a critical role in regulating metabolism. This is particularly interesting because the POMC neurons are among the most sensitive to decline during aging. To begin to directly test the role of specific gene products in the development of obesity, diabetes, and aging, we have now produced several lines of transgenic mice that overexpress leptin, POMC, insulin, and glucokinase specifically in the brain, and we are now assessing the effects of these transgenes in obesity, diabetes, and aging. For example, we have now shown that transgenic enhancement of neuronal POMC will completely correct the diabetes and other impairments in genetically obese mice. These studies have led to discovery of a new class of anti-obesity drugs that we are now studying. A new direction in our laboratory involves examining function of metabolic genes we have discovered using microarrays using RNA interference protocols in mice and in C. elegans. Using high-throughput RNAi screening methods we have discovered over 20 novel genes that regulate obesity in C. elegans. Using a similar approach we have also discovered a transcriptional complex that mediates the protective effects of dietary restriction to increase lifespan and protect against age-related diseases, including Alzheimer-type pathology and diabetic complications. Pharmacological activation of this pathway increases lifespan and protects against neurodegenerative diseases, and the same complex predicts lifespan and obesity in mice. We have now also developed novel high-throughput methods to discover novel anti-obesity and anti-diabetes drugs, and have discovered over 20 drugs in each class so far.
What is the hypothesis?
A key observation about the nature of age-related impairments is that these impairments accrue over time, reflecting a cumulative and apparently irreversible process. We have now discovered the molecular mechanism of this "molecular memory" effect and shown that it applies to all age-related diseases that are influenced by dietary restriction. In particular this process explains the cumulative development of diabetic complications, and implies that both age-related impairments and diabetic complications can not only be slowed (as with dietary restriction) but can actually be reveresed, by blocking glucose metabolism more effectively than can be done with dietary restriction. Further reading.
What are the projects?
Determine molecular mechanisms mediating the following observations:
AGINGReversing aging by enhancing a novel CBP transcriptional complex
Reversing aging with a ketogenic diet.
Reversing aging by activating the "glucose-switch" gene pattern
Reversing age-dependent deleterious changes in gene expression
OBESITYReversing obesity and diabetes with a humanized FGFR1c receptor antibody.
Reversing obesity and diabetes caused by CtBP inhibition.
Reversing obesity and diabetes caused by CBP overexpression.
Reversing obesity and diabetes caused by CREB overexpression.
Reversing obesity and diabetes with a ketogenic diet.
Reversing obesity and diabetes by inhibiting hypothalamic genes that predict obesity.
Reversing obesity by inhibiting hypothalamic genes whose inhibition reverses obesity in C. elegans
Reversing obesity in mice by drugs that reverse glucose-dependent obesity in C. elegans.
DIABETESReversing diabetic complications with drugs that block glucose neurotoxicity
Reversing diabetic complications with a ketogenic diet
ALZHEIMER'S DISEASEReversing Alzheimer's disease with drugs that prevent neurodegeneration.
Reversing Alzheimer's disease by enhancing a novel CBP transcriptional complex
Extending lifespan and preventing age-related diseases by enhancing activity of a novel CBP transcriptional complex.
What are the protocols?
- Genetic engineering (transgenic and knockout)
- Genetic manipulation by in vivo gene transfer: AAV and nanoparticles
- Complete metabolic phenotyping:
- Food intake
- Metabolic rate (indirect calorimetery)
- Temperature telemetry
- Tissue analysis
- Lifespan analysis
- Oxidative stress
- Functional screen by high-throughput RNAi
In cell culture
- High-content analysis
- Metabolic pathways
- Gene expression (RT-PCR)
Ko F, Isoda F, Mobbs C. Laparotomy in Mice Induces Blood Cell Expression of Inflammatory and Stress Genes. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2014.
Our laboratory studies the molecular basis of aging and age-related diseases, especially metabolic diseases such as obesity and diabetes, and related neurodegenerative diseases.