I’m thrilled to be sitting in the audience of the 17th Bay Area Aging Meeting, a conference that began (as the “Bay Area Aging Club”) back when I was a postdoc at the Buck Institute for Research on Aging. As interest in the topic has grown, the event has expanded accordingly. The UCSF organizer, Prof. Hao Li, just told me that nearly 500 people registered, with around 200 from biotech and pharma. I can’t think of a better illustration of how much momentum and excitement geroscience is generating, both in academic research and in industry.
I’ll be liveblogging the conference throughout the day — this post is just the starting point, so it will evolve significantly and probably calve off specialized posts about individual sessions. For now I’ll just be taking notes below, and as new articles are created I’ll link to them here.
Thanks for joining us!
For more coverage of BAAM 2018, see
In opening remarks, Professor Hao Li of UCSF explained the purpose of the meeting:
The purpose of the semiannual Bay Area Aging Meeting (BAAM) is to stimulate the advancement of aging research, promote its application to human health and to connect scientists throughout the Bay Area to facilitate collaboration.
“I feel that we have come to a historic moment — that rejuvenation has become a reality rather than fiction,” Professor Li said, “I also feel that there has never been a better time than now, or a better place than the Bay Area, to get involved in this field.”
He then passed the podium to Ann Brunet, chair of the first session.
Immune System and Brain Aging (Anne Brunet, chair)
Paras Minhas (Andreassen lab/Stanford) “Metabolically reprogramming innate immune cells in aging and inflammation”
Two major molecular events underlie Alzheimer’s disease (AD): accumulation of tau and Aβ, which are both cleared by the innate immune system. NSAIDs can help to prevent AD, but because of their side effects, these drugs can’t be given to geriatric patients chronically. Therefore, the Andreasson lab is looking at downstream targets of NSAIDs to try to reap the preventive medicine benefits while avoiding adverse effects.
Among other things found that de novo NAD+ synthesis is suppressed in aging innate immune cells, and conversely that overexpression of factors involved in this pathway suppresses inflammation. As we age, we accumulate misfolded proteins and downregulate immune metabolism, and this results in loss of the ability to clear pathogenic aggregates such as tau and Aβ.
Adelaida Palla (Blau lab/Stanford): “Overcoming inflammaging to augment muscle strength through stem cell expansion”
The next talk provided some insight into why long-term exposure to NSAIDs might be deleterious to the elderly: signaling by the prostaglandin PGE2 is required for the function of muscle stem cells, and inhibiting PGE2 signaling with NSAIDs or genetic knockout accelerates the decline in muscle strength with age. Conversely, PGE2 treatment increases the survival of aged muscle stem cells in vitro.
Even more exciting, intramuscular injection of PGE2 restores the regenerative capacity of aged muscle stem cells in vivo, increasing their capacity to regenerate in response to injury. Together, these findings indicate that PGE2 is an essential mediator of muscle stem cell regeneration.
David Furman (Visiting Associate Professor/Stanford): “Immunological Mechanisms of Aging and Chronic Disease”
Chronic diseases are the #1 killer worldwide, costing millions of lives and trillions of dollars every year. Chronic systemic inflammation is a central underlying cause of many of these disorders. This is distinct from acute local inflammation, which is short-term and promotes tissue repair. By contrast, chronic systemic inflammation is persistent and damages the tissue.
To search for biomarkers of chronic systemic inflammation, Furman’s lab monitored 1000 people over many years, and applied deep learning approaches (specifically an “autoencoder”) to crunch the data. They generated a GAE-based method for predicting the biological age of a subject based on the levels of inflammatory mediators called cytokines. This “inflammatory age” correlates much better with multi-morbidity (i.e., the propensity to develop multiple life-threatening age-related diseases) than chronological age.
Even in a population with no known risk factors for cardiovascular disease, a single inflammatory factor correlated with cardiovascular aging: CXCL9, produced by aging endothelial cells, which suppresses the pro-longevity protein SIRT3. (SIRT3 also came up in the question sessions of Paras Minhas’ talk; hoping to come back and fill this in later from my notes.)
Furman is planning follow-up studies in which inflammatory age is compared with other aging “clocks” such as DNA methylation.
Peter Sudmant (Assistant Professor/Berkeley): “Perturbations of RNA metabolism in specific neuronal populations of the aging brain”
Sudmant, a new professor at Berkeley, is interested broadly on the genomics of aging, but focused today on post-transcriptional gene regulation. The problem that motivated him is selective neuronal vulnerability: As we age, we are more likely to get neurodegenerative diseases, but for unknown reasons these disorders target specific cell types within the brain. Could post-transcriptional phenomena explain this selectivity?
In particular, he focused on the striatum (which is affected in Parkinson’s disease), using a technique known as translating ribosome affinity purification (TRAP) to identify differences in RNA metabolism in D1 and D2 dopaminergic neurons. Surprisingly, he found that D1 neurons specifically accumulated isolated 3’ untranslated regions (UTRs), the non-coding termini of mRNAs.
Why the selectivity? Are D1 neurons special in some way? Indeed, oxygen radicals and certain kinds of age-related markers like lipofuscin accumulate more rapidly in these cells. Sudmant proposes that under aging or related stresses, ribosomes stall on mRNAs, and the unique environment within D1 cells causes the 3’UTRs to be cleaved off.
The 3’UTRs end up getting translated into peptides (that should never have been made in the first place), potentially contributing to age-related decline in tissue function.
Tara Tracy (Assistant Professor/Buck) : “Spatiotemporal Mapping of the Tau Interactome to Investigate mechanisms in Alzheimer’s Disease”
Tau, which accumulates in Alzheimer’s disease (AD), is released from neurons in response to activity, leaving presynaptic neurons and possibly entering postsynaptic neurons—providing a mechanism by which the disease state could spread from cell to cell. What is the mechanism underlying this activity-dependent release?
Tracy proposed that under enhanced neuronal activity, tau associates with the cytosolic side of synaptic vesicles in association with SNARE complexes, and may penetrate the membrane. To study the membrane, her lab used a proximity-dependent labeling approach to identify tau- and tubulin-associated proteins.
The tau-specific proteins were highly enriched in vesicle and synaptic components, providing strong circumstantial evidence that tau is associted with synaptic vesicles in presynaptic neurons. Moreover, some of them were specific for enhanced activity, suggesting that these factors might be involved in membrane penetration and activity-dependent tau release.
Single Cell/New Technology (Chair, Danica Chen)
Guo Huang (Assistant Professor/UCSF) : “Molecular Control of Heart Regeneration: Insights from Long-lived Species”
Many species with diploid cardiomyocytes (CMs) live a long time. What is the basis of this relationship? Huang told us that it might involve thyroid hormone: high levels of TH appear to restrict cardiac regenerative capacity. The percentage of diploid CMs is inversely correlated with body temperature and basal metabolic rate (BMR) , which in turn scales with mass.
But why did evolution limit cardiac regeneration in the first place? This question remains open. One argument (Goss, 1969) is that regeneration may have disappeared as other physiological attributes evolved with which it may have been incompatible. Thyroid hormone may provide the key link. Huang suggested that elevation of thyroid hormone promotes acquisition endothermy and loss of heart regenerative potential.
Abby Buchwalter (Assistant Professor/UCSF) : “Nucleolar expansion in premature and physiological aging”
The nuclear periphery helps to organize the genome, and assembly of the nuclear lamina is disrupted in a rare premature aging syndrome called Hutchinson-Gilford progeria. Buchwalter set out to determine whether the lamina protein mutated in HGPS, lamin A, accumulates during progeria. Using metabolic labeling to track protein stability, she learned that lamin A and many other proteins are actually turned over more rapidly in patients with progeria.
Following up, she showed that progeroid cells are synthesizing more net proteins than normal cells, requiring greater turnover to achieve homeostasis. This upregulation of protein synthesis may explain, to some extent, the documented loss of heterochromatin in progeroid cells. Indeed, demethylation of repetitive rDNA loci in progeroid cells is dramatically reduced, causeing ribosomal RNAs to be produced at a higher rate. Similarly, more ribosomal proteins are produced, and the rRNAs and RPs get together to create more ribosomes, which in turn lead to higher overall rates of translation.
In progeria, then, we have a widespread disruption of heterochromatin marks, which derepresses rDNA loci and increases the rate of protein synthesis. This causes nucleoli, the site of rRNA production, to expand.
We know that decreasing ribosome biogenesis increases the lifespan. New data from Buchwalter’s lab shows that nucleoli also expand in normal aged individuals — and this phenomenon is conserved in worm, fly, and mouse. For example, in worm, nucleolar size is impressively negatively correlated with lifespan: large nucleoli on the first day of adulthood means a shorter life.
Denis Titov (Assistant Professor/Berkeley): “New tools for studying the role of energy metabolism in physiology and disease”
Energy metabolism is important for health and disease. For example, calorie restriction extends the lifespan of organisms from yeast to monkeys. Similarly, exercise is associated with a decrease in all-cause mortality in humans. We know many of the metabolic changes associated with these processes, but we don’t know which of these changes in bioenergetics are causative (i.e., sufficient to achieve the life-extending effects).
To study these ideas, the Titov lab is developing genetically encoded tools for manipulation of metabolism (GEMMs). Using one such tool, LbNOX, they can alter cytosolic and mitochondrial NADH levels and NADH/NAD+ ratios. The same tool can be used to complement dysfunction in the electron transport chain.
The lab is now applying GEMMS to study energy metabolism in mammalian cells and C. elegans, using the tools for compartment and tissue-specific manipulation of bioenergetic parameters.
Changhui Deng (Li lab/UCSF): “A high-throughput screening platform for discovering longevity genes and anti-aging drugs”
Budding yeast has served as a valuable model for aging research for many years, and continues to provide critical insights into the aging process today. In this talk, Deng focused on replicative lifespan: the number of times a mother yeast cell can produce a daughter cell before permanently ceasing division.
The Li lab has developed a microfluidic dissection platform for single-cell aging studies. Daughter cells are continuously removed, while the mother cell remains in her chamber, allowing the researchers to count the number of divisions from a single mother and monitor other aspects of the aging process. However, this method was somewhat low-throughput.
To improve their throughout, the lab developed the Daughter Arresting Program (DAP), a genetic manipulation that makes daughters unable to divide — this means that cell number increases linearly with time, and the replicative age of the mother can be calculated by simply counting the number of cells in a microcolony.
They adapted the DAP system to a high-throughput device for measuring lifespan, which can theoretically follow more than 7000 mothers per plate. Daughter cells are automatically counted using a machine learning approach.
They used the new system to screen for mutations that extend or limit lifespan, yielding dozens of novel longevity-associated genes. Using a DAmP approach (“decreased abundance by mRNA perturbation”), they were also able to examine the influence of essential genes on lifespan, and found some with significant effects.
Similarly, the system can be used to screen for drugs that extend lifespan. Among others, they found that spermidine, rapamycin, and NMN (all implicated as anti-aging drugs in larger organisms) extend replicative longevity in yeast. (The high-throughput nature of the system makes it a snap to optimize dose.)
The afternoon sessions are covered in a separate post, here.