Louis Lapierre proposed a hypothesis: aging begins when proteins lose their proper locations within the cell

Louis Lapierre proposed a hypothesis: aging begins when proteins lose their proper locations within the cell

In a perspective published on July 13 in Aging Cell, Lapierre brought together existing evidence on nuclear transport into a single hypothesis. He proposes that age-related dysfunction of karyopherins, the proteins that transport cargo between the nucleus and cytoplasm, both disrupts protein function and increases the risk of protein aggregation.

Proteostasis is the set of processes by which a cell keeps its proteins functional. It helps proteins fold correctly, prevents them from aggregating, and breaks down damaged molecules. Lapierre adds the cell's internal geography to this framework. A protein can fold correctly but still end up in a compartment where the partners it needs are absent. The nucleus and cytoplasm have different chemical environments, so the same molecule can behave differently in each compartment.

Nuclear pores and karyopherins maintain this spatial organization. Small molecules pass through the pores on their own, while many proteins require a carrier. Some carriers do more than deliver cargo. The import karyopherin KAPβ2 provides one example. It binds FUS, a protein that accumulates in cells in some forms of amyotrophic lateral sclerosis, at several sites. In experiments, KAPβ2 kept FUS soluble and extracted it from aggregates that had already formed. This example involves one KAPβ2–FUS pair: the carrier both directs the protein to its proper location and prevents it from aggregating.

Lapierre proposes that long-lived components of nuclear pores may accumulate damage over time. Karyopherins would then become less effective at transporting or retaining their cargo, leaving proteins outside the compartments where they normally function. Protein aggregates can themselves slow transport between the nucleus and cytoplasm. This leaves two possible causal sequences: transport failure may be an early defect, or it may result from earlier damage.

One experimental line of evidence for this idea already exists. In a 2018 study, partial suppression of xpo-1, the nematode counterpart of the exporter XPO1, increased mean lifespan in adult nematodes by approximately 15–45%. Suppression earlier in life shortened lifespan. In a 2022 study, a group that included Lapierre found that the intervention changed protein distribution, reduced nucleolar size, and lowered overall protein synthesis. The method captured both direct transport defects and changes in protein turnover within the nucleus and cytoplasm in the same way, so it could not establish which occurred first.

The next experiment could test the hypothesis by examining a single carrier to cargo route in a defined tissue. It would need to establish the sequence of events by showing that transport fails before other age-related changes occur. It would also need to show that precise restoration of this route prevents damage and preserves the remaining transport network. If those conditions are met, Lapierre's spatial hypothesis would become a testable causal model of aging.