Deep dive Q&A: Ania Puszynska discusses how aging affects cells’ recycling centers

Lysosomes, the cell’s recycling hubs, are best known for their role in a group of rare inherited conditions called lysosomal storage disorders, where harmful molecules build up inside these compartments. But scientists are increasingly realizing that these organelles play a much broader role in health and disease: problems with lysosome function are also seen in more common, age-related conditions like Alzheimer’s and Parkinson’s disease.

Ania Puszynska, a postdoctoral fellow in the lab of Whitehead Institute Member Jonathan Weissman, is exploring how aging affects the way our cells function. At the center of her research are lysosomes and a decades-old question: how do these organelles change with age? Answering this question would help scientists better understand why — and exactly how — aging increases our risk of developing certain diseases, including neurodegenerative disorders.

We sat down with Ania to learn more about the role lysosomes play in the cell, how these organelles change as we age, and why those changes matter for understanding the biology of age-related diseases.

This interview has been edited for length and clarity.

Whitehead Institute: Scientists have long suspected that lysosomes undergo changes during aging. Why has it only recently become possible to answer this question?

Ania Puszynska: The question of how lysosomes change during aging is actually a very old one. Christian de Duve, the scientist who discovered lysosomes in the early 1950s, proposed just a decade after discovering them that lysosomes change as we age. At the time, though, there was little evidence to support the idea. The hypothesis continued to come up over the years as scientists thought about aging and lysosomal biology but the field lacked the tools to test it directly.

When I joined Whitehead Institute, I found that my lab had the latest tools that would make it possible to tackle this long-standing question in a way that hadn’t been possible before. Using these tools, we could isolate and remove lysosomes from many different types of tissues and analyze them directly. This gave us an incredible opportunity to systematically examine how lysosomes change as we age.

WI:  What roles do lysosomes play in the cell, and what got you interested in studying them?

AP: Lysosomes are organelles responsible for breaking down and recycling many different kinds of molecules. Material is brought into the lysosome, where it’s broken down into smaller components that can then be recycled back into the rest of the cell. They’re also important signaling hubs that help cells make decisions about how to manage nutrients and respond to changes in their environment.

During my Ph.D. I studied how bacteria coordinate metabolism to adapt to changing environments. That experience left me fascinated by a broader question: how do more complex cells organize metabolism across organelles – or specialized structures – in a cell? When I began thinking about organelles, lysosomes immediately stood out. Their ability to connect recycling, nutrient availability, and cellular adaptation made them a fascinating system for studying how cells maintain metabolic balance. 

WI: You’ve been looking at how the molecular composition of lysosomes changes as we age. Can you tell us more about your research?

AP: To understand how these organelles change with age, I examined lysosomes from 12 different tissues in both female and male mice. In four tissues — the brain, heart, skeletal muscle, and fat — I found higher levels of two groups of molecules, or metabolites, in the lysosomes of older animals. 

What’s surprising is that these same molecules are known to build up in lysosomal storage disorders, where the organelles can no longer properly break down or clear certain materials. This suggests that aging lysosomes may share some molecular features with lysosomes affected by disease.

The important question now is whether the levels of these molecules observed during normal aging have any biological consequences. For example, whether they affect how lysosomes function or influence the health of the cell — we just don’t know that yet. If we discover that their accumulation does influence cell or lysosome function, then researchers could begin searching for ways to reduce this accumulation as a way to improve the function of aging cells. 

I also found that these molecules track with chronological age, meaning they accumulate in a very predictable way within the lysosomes as the animal gets older. This suggests these molecules could serve as a molecular marker that reflects the chronological age of the organism. Readers can find out more about this work in my recent Science paper.

WI: Within the brain tissue, which cell types showed the greatest accumulation of these molecules?

AP: I looked at four major brain cell types and found that neurons and microglia, the brain’s immune cells, showed the strongest increases in these molecules. One possibility is that microglia are especially vulnerable because they act as the brain’s “cleanup crew”. They’re constantly engulfing and breaking down debris, including damaged material that builds up with age. Neurons are also interesting because they’re incredibly long-lived cells. They stay with us throughout our lives, so any changes that happen inside these cells have a long time to accumulate.

This finding certainly raises a lot of questions because both neurons and microglia are involved in many age-related neurodegenerative diseases. But we don’t know yet whether these lysosomal changes are contributing to disease risk or whether they’re simply a consequence of aging. That’s one of the big questions I want to understand: why are these particular cell types more affected, and what do these changes mean for the aging brain?

WI: Can these age-related changes be reversed? If not, what does that tell us?

AP: Caloric restriction is one of the best-studied interventions known to influence aging in many organisms. What I found was that caloric restriction made lysosomes appear more youthful in the heart and muscle, but not in the brain. 

One possible explanation is that the brain is protected during periods of limited nutrients. We know the body prioritizes supplying energy to the brain when resources are scarce, so perhaps the processes that reverse these changes aren’t activated in brain tissue to the same extent.

That’s still speculative, but it does suggest that different tissues may respond differently to the same intervention. Understanding why that is could be important for developing treatment strategies for age-related diseases, particularly those affecting the brain.

WI: What’s next for you? 

AP: I see this work as the beginning of a broader research program that I hope to pursue in my own lab. I would like to study the fundamental biology of lysosomes within tissues: how they adapt to different challenges, respond to stress, and ultimately influence whether cells remain healthy throughout life. 

Aging is one context in which lysosomes fail, but many neurodegenerative and metabolic diseases also involve lysosomal dysfunction. By understanding the basic principles that govern these organelles, I hope we can find new ways to preserve cell health across a broad range of diseases