Aging: Cellular Mechanisms and Therapeutic OpportunitiesBeginn: 29. Sept 15, 11:00 Uhr | Ende: 30. Sept 15, 21:00 Uhr | Schloss Herrenhausen
The conference discussed basic molecular processes and translational research approaches concerning cellular aging and its therapeutic countermeasures. Summary report by Holger Breithaupt.
It is not only human vanity that drives research into fending off the effects of aging: age-related diseases, such as cancer, cardiovascular diseases, Alzheimer’s or Parkinson’s disease, create a growing economic burden on health care systems as the population grows older. The 11th Herrenhausen Symposium on September 29 and 30, 2016 presented current research to understand the cellular mechanisms of aging and discussed therapeutic options to increase human life span and health in old age.
Stem cells play a crucial role in repairing damaged tissue; once their job is finished, they become quiescent again by breaking down proteins and removing mitochondria through a process called autophagy. Emmanuelle Passegué showed that, as autophagy diminishes in a fraction of older blood-forming stem cells, their ability to regenerate the blood system and replace immune cells decreases. This finding could lead to therapeutic options to improve immune function among the elderly.
Saul Villeda described the function of stem cells in the hippocampus, a brain area that plays a central role in learning and memory. With age, these cells lose their potential to create new neurons, which is one of the reasons for cognitive decline. Villeda’s research identified a molecular regulator of stem cell-driven regeneration; decreasing its concentration in the hippocampus increases the generation of neurons, and improves learning and memory.
Aging increases the risk of arteriosclerosis, heart failure or aneurysms. Stefanie Dimmeler explained that micro-RNAs – small molecules that fine-regulate protein production – control these processes, which could offer therapeutic options. Indeed, blocking specific micro-RNAs improves heart function, the formation of new blood vessels after infarct, and accelerates wound healing.
Mitochondria, the cell’s power plants, play a crucial factor in aging: when these organelles age, they damage other cellular structures. Toren Finkel described how mitophagy removes old mitochondria in cells and presented an assay to quantify this process. This test can be used to identify drugs that stimulate mitophagy in older cells.
Diet can extend life span and improve health in old age in animal models. James Mitchell showed that dietary restriction generates hydrogen sulfide, which decreases blood pressure and protects cells against environmental stress. This finding has potential for therapeutic use not only to increase healthy life span but also to protect against stress such as surgery.
Rafael de Cabo analyzed research on the health benefits of dietary restriction, the effect of which depends on genetics, sex and diet; monkeys do not live longer on average but have a lower risk of developing age-related diseases. He cautioned that it is premature to advocate dietary restriction or mimetic drugs thereof to increase health or life span in humans.
Linda Partridge, in her keynote talk, further detailed how diet affects aging processes through insulin, the main hormone that controls the availability of nutrients. Drugs to modify insulin pathways could thus induce health benefits. Partridge also showed that dampening insulin signals in the body ameliorates the effects of aging on neurons, which might help to prevent neurodegenerative diseases.
Longevity and fertility influence each other: sterilizing the worm C. elegans by removing the germline cells drastically increases the animal’s life expectancy. Adam Antebi’s investigation of this effect revealed a core longevity mechanism that controls different aging processes in many animals from worms to humans.
Telomeres are DNA sequences that protect chromosomes from damage; however they shrink with each cell division and thereby determine how often a cell can divide. Mary Armanios presented clinical research on people born with short telomeres who have a higher risk of developing an untreatable lung disease early in life. These patients are also more susceptible to environmental stress owing to their body’s impaired ability to repair lung tissue. Using telomere length as a marker could help clinicians to make better therapeutic decisions.
Another hallmark of aging is the change and distribution of epigenetic markers–chemical modifications of DNA and associated proteins–in the genome. Matthew Hirschey explained how diet influences these changes. He showed that the fatty acid octanoate reprograms cellular mechanisms and alters epigenetic markers in mitochondria; as such, it mimics the beneficial effects of dietary restriction.
Lenhard Rudolph described how aging leads to specific alterations in epigenetic responses to stress, thereby limiting the ability of stem cells to generate new cells in response to tissue damage in muscle. Similarly, Carolina Florian showed that, as the distribution of epigenetic markers in the genome changes with age, blood stem cells lose their ability to replace cells of the immune system.
John Sedivy described the global effect of epigenetic changes on gene activity and the three-dimensional architecture of chromosomes in senescent cells. Silent parts of the genome become active and with it so-called retrotransposons–descendants of retroviruses–which begin to copy themselves across the genome. Anti-retroviral drugs could therefore suppress retrotransposons and protect cells from associated DNA damage.
One therapeutic approach is to remove senescent cells, which secrete stress signals that can damage surrounding tissue and cause disease. Jan van Deursen presented experiments in mice showing that removing senescent cells caused an average increase of life span by 25% and increased health. Destroying senescent cells in humans could thus become a potential anti-aging therapy and also improve health in cancer patients after chemotherapy caused their cells to age prematurely.
Darren Baker discussed how senescent cells play a role in the initiation and progression of atherosclerosis. He showed that treating a mouse model with the drug ganciclovir prevented the accumulation of these cells in the main blood vessels and reduced the risk of atherosclerosis.
With age, the cell’s ability to optimize the production and breakdown of proteins (proteostasis) diminishes and protein aggregates begin to clog up the cell. Marie Lechler showed how old cells are no longer able to remove so-called stress granules that fine-regulate protein synthesis in times of crisis. Drugs that target this process could support aging cells to clean up protein aggregates.
Another therapeutic option is to make use of chaperones, proteins that help other proteins to fold into the correct structure. Bernd Bukau demonstrated how a specific set of chaperones in humans dissolves protein aggregates, including amyloid fibrils that cause neurodegenerative diseases such as Alzheimer and Parkinson.
The cell’s repair mechanisms to maintain proteostasis are usually limited to the affected organelle or cell compartment. Andrew Dillin presented a new stress-response pathway in mitochondria that triggers protein degradation in other cellular compartments.
Tilman Grune’s talk focused on the cell’s two major mechanisms to degrade proteins: proteasomes and autophagy. Too many protein aggregates in older cells can overwhelm the proteasome and escape autophagy. These aggregates become increasingly dense and are chemically modified to form so-called lipofuscins that damage the cell and further accelerate its aging.
Guido Kroemer explained how stimulating autophagy and thereby self-repair mimics the effects of dietary restriction such as weight loss and lowers the risk of diabetes. Autophagy-stimulating compounds include certain nutrients, such as spermidine, which is found in aged cheese, mushrooms, soy products and whole grains.
Yet, applications in the clinic remain rare because the topic suffers from a aging-disease dichotomy according to David Gems. While many scientists regard aging as a cause of disease, clinicians see it as a normal process. To reduce the burden of age-related diseases would require overcoming this dichotomy and clinicians should adopt a more scientific view of aging.
Joan Mannick showed data from preclinical trials how blocking specific aging processes improves immune function in elderly people. Karen Duff also demonstrated how increasing proteasome activity in the early stages of neurodegenerative disease can halt protein accumulation and restore cognitive function.
Despite all the progress, many challenges remain. Most knowledge is based on animal models and not always applicable to the human condition. Clinical research to address aging rather than specific diseases faces regulatory challenges and needs better markers to demonstrate success. Nonetheless, participants were confident that the first drugs against specific age-related conditions could become available within the next decade.
Adam Antebi (Max Planck Institute for Biology of Aging, Germany)
Mary Armanios (Johns Hopkins University, USA)
Bernd Bukau (Heidelberg University - ZMBH, DFKZ, Germany)
Rafael de Cabo (National Institutes of Health, USA)
Andrew Dillin (University of California, Berkeley)
Stefanie Dimmeler (Goethe University Frankfurt am Main, Germany)
Karen Duff (Columbia University)
Toren Finkel (National Institutes of Health, USA)
David Gems (University College London, UK)
Tilman Grune (Friedrich-Schiller-University Jena, Germany)
Matthew Hirschey (Duke University, USA)
Guido Kroemer (University of Paris Rene Descartes, France)
Joan Mannick (Novartis Institutes for BioMedical Research, USA)
James Mitchell (Harvard University, USA)
Linda Partridge (University College London and the Max Planck Institute for Biology of Ageing)
Emmanuelle Passegue (University of California, San Francisco, USA)
Karl Lenhard Rudolph (Leibniz Institute for Age Research, USA)
John Sedivy (Brown University, USA)
Jan van Deursen (Mayo Clinic College of Medicine, USA)
Saul Villeda (University of California, San Francisco, USA)
Kevin Da Silva