Cell maintenance

The cell’s recycling system doesn’t simply wind down with age, a study of human cells suggests

Autophagy, the way cells break down and reuse their own worn-out parts, is often said to decline with age. In cells from healthy volunteers it rose, fell or stayed flat depending on cell type and sex, and in people over 70 more of it was linked to poorer fitness. The groups were small and the exercise part was a five-person pilot.

Every cell produces waste: misfolded proteins and worn-out parts. One way cells deal with it is autophagy (Greek for “self-eating”). The cell wraps the rubbish in a small bubble of membrane, an autophagosome, and delivers it to the lysosome, a compartment full of enzymes that break it down into reusable building blocks.

Studies in lab animals, and of tissue from people after death, have suggested that autophagy weakens with age, and boosting it extends life in several lab animals. But measuring it in living people is hard. Counting autophagosomes doesn’t tell you much: a pile-up could mean the cell makes many, or fails to clear them. What matters is the flux, the rate at which material moves through the system. A team at the Sanford Burnham Prebys Medical Discovery Institute and UC San Diego measured that flux in several kinds of human cells from the same volunteers.

What they did

The volunteers came from a San Diego study of healthy adults of all ages who reported no chronic disease. They did fitness tests such as a treadmill test of maximal oxygen uptake, grip strength, walking speed and chair stands. The team studied three cell types from them:

  • Skin cells called fibroblasts, the cells that make connective tissue, grown from 44 donors.
  • Nerve cells made from those skin cells by switching on two genes (induced neurons), from 22 donors.
  • White blood cells from fresh blood, mainly lymphocytes, from 23 people.

To measure flux, they briefly added chloroquine, a drug that stops lysosomes from breaking things down (used here only on cells and blood samples in the lab). Autophagosomes then pile up; the bigger the pile-up compared with untreated cells, the higher the flux. In small groups of young and older donors they also read out which autophagy genes were switched on.

Finally, they tested five residents of senior living facilities, aged 77 to 88, before and after a 12-week fall-prevention program: one hour a week of balance, strength and posture exercises.

What they found

  • Genes and activity didn’t match. In skin cells from older donors, many autophagy genes were more active, not less, yet the actual flux did not follow the gene readings.
  • It depended on cell type and sex. In skin cells, flux fell with age in men but stayed stable in women. In the nerve cells it rose with age in women and stayed roughly flat in men. Within one person, flux in one cell type did not predict flux in another.
  • Blood cells varied more with age. Blood-cell flux was not clearly tied to age, but differed more between people as they got older, with a trend toward higher values from around 70.
  • Over 70, more flux went with weaker fitness. In participants aged 70 and over (10 people for the blood cells), higher blood-cell flux was linked to lower maximal oxygen uptake, slower walking and slower chair stands. Higher flux in skin and nerve cells from this age group also lined up with worse scores on some measures. Across all ages the picture was mixed: higher blood-cell flux was linked to a lower resting heart rate, usually a good sign.
  • The exercise pilot. At the start, 4 of the 5 older participants had blood-cell flux above the usual range of the healthy group. After 12 weeks it had dropped in 4 of the 5, into that range, and their score on a standard test of balance, walking and standing up improved. Grip strength, blood pressure and chair stands were unchanged. The one person whose flux rose was the youngest (77) and the fittest at the start.

What to keep in mind

  • Small numbers. The over-70 analyses rest on 6 to 10 people per cell type, and the authors say these links “should be interpreted cautiously”.
  • Links, not causes. The fitness findings are correlations at one point in time. The exercise pilot had five people and no group that did not exercise, so it cannot show that exercise caused the change. The authors call these findings “preliminary”.
  • Cells outside the body. Flux can’t be measured inside a living person this way. The skin and nerve cells were grown in dishes, and lab-made neurons may not behave like neurons in the brain.
  • What the test can’t see. The method tracks one autophagosome marker. It cannot tell whether the right cargo is being picked up or how well lysosomes work. Frailty itself was not measured with a validated scale.

Why it matters

The common story is that the cell’s recycling system simply runs down with age. This study points to something messier: in human cells it changed in different directions depending on cell type and sex, and in older people a busier system went with poorer fitness, not better. The authors suggest that high flux in old age may signal stressed cells working harder rather than a healthier system, which matters for drugs or diets meant to “boost autophagy”. Larger studies, also measuring frailty and memory, are needed to test this.

Sources