Bay Area Aging Meeting: Live coverage (PM sessions)
More than 500 people attended the 17th Bay Area Aging Meeting, with around 200 from outside of academia — including representatives from industry and the general public.

More than 500 people attended the 17th Bay Area Aging Meeting, with around 200 from outside of academia — including representatives from industry and the general public.

After a delightful morning session, a fascinating keynote by MIT’s Lenny Guarente, and a poster session that I didn’t even try to cover (but enjoyed immensely), we’re back for the afternoon talks.

For more coverage of BAAM 2018, see

Stress/Senescence/Rejuvenation (Chair: Pankaj Kapahi)

Helen Wong (Brand Lab/Buck): “Mitochondrial and cytosolic sources of hydrogen peroxide in cells”

Are reactive oxygen species (ROS) good or bad? It depends on the context. On the good side, these compounds regulate cellular signaling and physiological responses, but on the bad side, they can promote oxidative damage. To reconcile these somewhat contradictory findings, researchers have proposed that low levels of ROS are favorable, whereas high levels are deleterious.

Sounds reasonable, right? Unfortunately, right now there’s no clear definition of “low” and “high,” enabling anyone to fit their story into that very broad picture. To refine the model, Wong proposes that we should think about the proximity of ROS generation to various cellular components. After all, an oxidative molecule that is generated next to an oxidation sensor will have a very different effect than one generated next to a highly susceptible, physiologically important molecule. Moreover, it is necessary to define the relative contributions of different sources of ROS.

Yiwen Chen (Jarosz lab/Stanford): “Prion-like aggregation in an aging vertebrate proteome”

As we age, the rate of protein aggregation rises along with the incidence of degenerative conditions, and it is widely accepted that loss of proteostasis is a hallmark of aging. But what is the relationship between protein aggregation and “normal” aging?

Experimental work on this question in model systems evolutionarily close to humans has been hampered by the fact that vertebrates have such long lifespans—but enter the killifish, which lives only 6 months, enabling lifespan studies to be completed much more quickly than in conventional model systems.

Using killifish, Chen has detected age-associated changes in aggregation for particular proteins, identifying one or a few dozen proteins in each tissue that exhibit a significant age-related increase in aggregation propensity.

In functional terms, each tissue seems to exhibit aggregation in specific pathways, e.g., RNA binding proteins tend to aggregate in liver, but not in other parts of the body. However, not all of these aggregated proteins are inherently toxic.Strikingly, in brain, the proteins that aggregate have a strong tendency to be prion-like.

Fatouma Alimirah (Campisi Lab/Buck): “Chemotherapy-induced Cellular Senescence Drives Skin Carcinogenesis”

Why do so many tumors relapse after chemotherapy, sometimes years after treatment? The answer may have to do with cellular senescence—which, somewhat ironically, evolved as a tumor suppressor mechanism.

Senescent cells secrete a host of factors called the senescence-associated secretory phenotype (SASP), a subset of which can drive cancer growth. Chemotherapy, it turns out, can induce senescent cells to accumulate. Could the factors produced by senescent cells created by chemotherapy cause other cells to become cancerous?

To address this question, Almirah induced senescence in mouse skin using the chemotherapeutic agent doxorubicin, which damages DNA, but then used a genetic trick to eliminate the senescent cells in some of the mice. She then subjected the mice to a two-step carcinogenesis model (induction of a RAS mutation, followed by a mitogen), and asked whether the presence of senescent cells prior to tumor initiation affected tumor growth.

Elimination of senescent cells dramatically decreased tumor size, implying that senescence induced by a prior course of chemotherapy can act as tumor promoters in skin cancer. The strong implication is that removal of chemotherapy-induced senescent cells will help to discover novel alternative therapies against cancer.

Amit Sharma (Kapahi Lab/Buck): “Inhibition of ADAM19, a metalloprotease, not only modulates survival and healthspan in flies under genotoxic stress but also acts as a gatekeeper to modify the SASP and senescence in human cells”

ADAMs are highly conserved membrane proteins that mediate release of cytokines and other factors from the cell curface. Knockdown of one family member, ADAM19, decreases irradiation-induced intenstinal permeability and apoptosis in flies, and phamaceutical inhibition of the protein had a similar effect in mice.

Moreover, ADAM19 inhibition decreased cellular senescence in human fibroblasts, downregulated the SASP, and changed the composition of cytokines and growth factors secreted by senescent cells. Pharmaceutical induction of autophagy also decreased expression of SASP factors.

Chao Liu (Conboy lab/Berkeley): Bio-orthogonal identification of rejuvenative and pro-aging proteins

Heterochronic parabiosis—in which the circulatory systems of a young animal and an old animal are connected is an effective (if somewhat grisly) way to delay the process of certain aging-related processes. But which of the proteins in the tissues of parabiotically connected animals are derived from the circulation ofthe young vs. old partner?

This could be addressed by biochemical fractionation, but that would be labor-intensive and prone to various kinds of failure modes. Instead, the Conboy lab has adopted another approach: bio-orthogonal chemistry, which refers to techniques for modifying biomolecules in ways that enable them to be differentiated without interfering in any way with their functions.

These techniques enabled Liu to identify several “young” systemic factors in regenerating muscle of the old parabiotic partner. They have also developed a graphene-based chip system for rapid detection of labeled proteins in their samples.

Jay Goodman (Unal lab/Berkeley): “Cellular rejuvenation in meiosis: how to create life out of programmed death”

As yeast age, the mother cells accumulate senescence factors in their nuclei (protein aggregates, extrachromosomal ribosomal circles [ERCs) that ultimately interfere with physiological and replicative functions. But how do these factors behave during meiosis, when the replicative history is erased and the cell is rejuvenated?

It turns out that both aggregates and ERCs are sequestered away from dividing nuclei during anaphase II, and subsequently eliminated during gamete maturation. Old cells have expanded nucleoli, but seem to be able to sequester more nucleolar material than young cells during anaphase.

Interestingly, the nuclear pore complex is sequestered along with age-induced damage, and the bodies containing NPC components and senescent factors end up in the ascus, but are excluded from the individual gamete cells themselves.

How, then, are the NPCs and age-related damage destroyed? One possibility is that vacuolar lysis during gamete maturation releases degradative enzymes that destroy the extracellular bodies where the factors are sequestered. The entire process seems to be organized by a protein called Spo21, which controls gamete plasma membrane formation.

Whew…my fingers are tired. There’s a panel discussion coming up, but I’m going to record it, tweet a bit (at @HourglassBio, using hashtag #BAAM18), and write about it later. Thanks for following our coverage of the research talks, and watch this space for posts about Lenny Guarente’s keynote and the panel discussion, coming next week!