Here - American Geriatrics Society

P APER
A BSTRACTS
ent. We hypothesize that resveratrol may be acting through SIRT-1,
which in turn inhibits p53-regulated senescence. Because colon cancer
is a disease whose incidence rises with age, the ability of resveratrol
to inhibit senescence and the aging process in colonic mucosa will
potentially have profound applicability to colon cancer prevention.
P17
The Role of SIRT3-dependent Autophagy in Age-Related
Hearing Loss.
I. Pena , F. A. Pereira. Huffington Center on Aging, Departments of
Otolaryngology-HNS and Molecular & Cellular Biology, Baylor
College of Medicine, Houston, TX.
Supported By: American Federation for Aging Research / Medical
Student Training in Aging Research Program, The Oticon
Foundation / The American Academy of Otolaryngology–Head &
Neck Surgery Foundation, Huffington Center on Aging–Baylor
College of Medicine.
Background: In 2005, the WHO estimated that 278 million people
suffered moderate-to-profound hearing impairments. This number is
expected to reach 900 million people by 2050, creating immense socioeconomic
burdens worldwide. Age-related hearing loss (AHL), a
disorder associated with accumulated cellular oxidative damage, affects
more than 40% of Americans over age 65. The mitochondrial
deacetylase SIRT3 improves antioxidant defenses by activating isocitrate
dehydrogenase 2, thereby increasing the reduced-to-oxidized glutathione
ratio. Oxidative stress induces autophagy, a process by which
cells degrade and recycle their contents to preserve cellular health.The
precise molecular mechanisms by which cells respond to oxidative
stress and induce autophagy via SIRT3 have not yet been elucidated.
Methods: We investigated the role of SIRT3 in regulating autophagy
in model systems. We used inner ears, brain, heart, and fibroblasts
from wild type (WT), SIRT3-overexpressing, and Little
mice (have 40% longer lifespan and reduced oxidative stress). Experiments
included activation and inhibition of autophagy and expression
of SIRT3 to determine its potential role in SIRT3-dependent
protective mechanisms against cellular damage and AHL.
Results: The average SIRT3 levels were increased 18% in 24-
month-old WT mice and increased 628% in 24—month-old Little mice,
compared to their 4-month-old littermate controls.When SIRT3 levels
were depleted in WT fibroblasts using siRNA, autophagy was activated
as measured by LC3-II/LC3-I ratio. After an 18- or 24-hour treatment
with 100nM rapamycin, autophagy levels also increased 1.8-fold while
SIRT3 levels decreased 1.37-fold.Activating autophagy by 2 or 4 hours
of starvation increased activation 8.35-fold and SIRT3 levels decreased
3.9-fold. Inhibiting autophagy with 50uM Wortmannin for 2 or 4 hours
decreased autophagy 2.78-fold and increased SIRT3 levels 1.35-fold.
Conclusion: These preliminary results suggest autophagy is
linked to SIRT3: increased SIRT3 is associated with improved oxidative
protection and decreased autophagy and vice versa. These findings
may provide therapeutic insight into rational drug design of new
medications that activate SIRT3 or autophagy for the prevention of
age-related hearing loss and to improve health span.
P18 Encore Presentation
Lipid-depleted apolipoproteins and amyloid peptides are influenced
by APOE genotype and cognitive diagnosis.
A. J. Hanson, 1,2 J. L. Bayer-Carter, 1,2 P. S. Green, 1,2 T. J. Montine, 1,2
L. D. Baker, 1,2 G. S. Watson, 1,2 L. M. Bonner, 2 M. Callaghan, 2
J. B. Leverenz, 1,2 B. K. Walter, 2 E. C. Tsai, 1,2 C. W. Wilkinson, 1,2
J. Zhang, 1 S. Craft. 1,2 1. University of Washington Medical Center,
Seattle, WA; 2. GRECC, VA Puget Sound Health Care System,
Seattle, WA.
Supported By: T32 AG-000258-13 to Dr. Hanson, R37 AG-10880
from NIA to Dr Craft, P50 AG-05136 to Dr. Montine.
BACKGROUND: Sporadic Alzheimer’s disease (AD) is caused
in part by decreased clearance of the Aβ amyloid breakdown products.
Apolipoproteins play an important yet unclear role in Aβ peptide
clearance, particularly ApoE since its E4 variant is a risk factor
for AD. Work in cell culture and animal models have shown that
lipid-depleted apolipoproteins are less effective at binding Aβ, and
that lipoprotein-depleted (LD) fractions of Aβ peptides are more
toxic to neurons. However, not much is known about the lipid states
of these proteins in human CSF.
METHODS: Cerebrospinal fluid (CSF) was obtained from 20
participants with normal cognition (mean age 69 ± 7) and 27 with
amnestic mild cognitive impairment (MCI) (mean age 67 ± 6). We determined
the APOE genotype status of each participant. Lipid-depleted
ApoE and ApoJ and lipoprotein-depleted Aβ peptides were
separated by density gradient ultracentrifugation and levels were
then measured by ELISA. Groups were compared using analysis of
covariance.
RESULTS: Subjects with an APOE ε4 allele (E4+) had higher
lipid-depleted ApoE levels, for both normal and MCI groups
(p