Nat Aging: Increasing levels of lamin C is expected to slow cardiac aging

Cardiovascular disease is the leading cause of death worldwide, partly due to
age-related structural heart dysfunction.
In a new study, Professor Adam Engler and his research team from the University of California, San Diego, published a paper in the journal Nature Aging on December 22, 2022, titled "Age-dependent Lamin changes induce cardiac dysfunction via dysregulation of cardiac transcriptional.
" programs" paper helps advance understanding of how the heart ages and reveals possible ways
to slow cardiac aging.

Dr.
Natalie Kirkland, the first author of the paper and a postdoctoral scholar in Engler's lab, used fruit flies to conduct experiments and found that lamin C (LamC), a protein responsible for maintaining the structural integrity of the nucleus of heart cells, declines
with the aging of fruit flies.
The new study found that the decline in lamin C is responsible for age-induced structural remodeling in the hearts of fruit flies, so it may be a potential target for slowing or even helping to reverse aging in human
hearts.

Kirkland said, "Our study shows that age-dependent nuclear remodeling plays a key role
in heart function.
Nuclear morphology may be a marker of cell and tissue health and may be a target for the development of potential therapies
.
”

The authors used Drosophila melanogaster as subjects in this study for several reasons: (1) Drosophila melanogaster has a lifespan of between 6 and 8 weeks, which makes them useful for age-related studies; (2) Fruit flies and humans have 82% of the same heart proteome; (3) Drosophila genetics is simple and easy to simulate
.

These properties make Drosophila a relatively fast and simple model to determine the cardiac preservation pathways
of interest to human studies.
Kirkland and co-author Scott Skalak used a microdissection technique
on the heart of fruit flies.
Their hearts are then preserved and examined
with immunofluorescence and confocal microscopy.
"This is the first time I've observed that the nuclei of the heart cells of aging fruit flies are shrinking and becoming more rounded
," Kirkland said.
”

The authors then quantified this change
by segmenting and measuring the hardness of the nucleus with atomic force microscopy.
At this time, they found that the nuclei of cardiomyocytes hardened during the natural aging process; After genetic analysis, they found that as fruit flies aged, the amount of lamin expression in the nucleus decreased
.

Natural aging downregulates LamC and LamB without affecting their localization
.
Image from Nature Aging, 2022, doi:10.
1038/s43587-022-00323-8
.

In addition, the authors were able to verify that these results also apply to mice and primates
.
This suggests that the effects of lamin may also be applicable to cardiac aging in humans, which could have great therapeutic value, as targeting lamin-stimulated pathways may potentially help avoid this mechanical change
associated with cardiac aging.

"We found the role of cardiac transcription factors in regulating contractility in adults and showed that maintaining the expression of lamin C and cardiac transcription factors prevents age-dependent cardiac decline
," the authors wrote.
Our findings are consistent in older non-human primates and mice, suggesting that age-dependent nuclear remodeling is a major mechanism
leading to cardiac dysfunction.
”

Future research will explore why lamin is lost with age and how maintaining the expression of certain heart genes can improve heart function and longevity
.
(Biovalley Bioon.
com)

Resources:

Natalie J.
Kirkland et al.
 Age-dependent Lamin changes induce cardiac dysfunction via dysregulation of cardiac transcriptional programs.
Nature Aging, 2022, doi:10.
1038/s43587-022-00323-8.