Sporadic premature aging in a Japanese monkey: a primate model for progeria

Abstract

In our institute, we have recently found a child Japanese monkey who is characterized by deep wrinkles of the skin and cataract of bilateral eyes. Numbers of analyses were performed to identify symptoms representing different aspects of aging. In this monkey, the cell cycle of fibroblasts at early passage was significantly extended as compared to a normal control. Moreover, both the appearance of senescent cells and the deficiency in DNA repair were observed. Also, pathological examination showed that this monkey has poikiloderma with superficial telangiectasia, and biochemical assay confirmed that levels of HbA1c and urinary hyaluronan were higher than those of other (child, adult, and aged) monkey groups. Of particular interest was that our MRI analysis revealed expansion of the cerebral sulci and lateral ventricles probably due to shrinkage of the cerebral cortex and the hippocampus. In addition, the conduction velocity of a peripheral sensory but not motor nerve was lower than in adult and child monkeys, and as low as in aged monkeys. However, we could not detect any individual-unique mutations of known genes responsible for major progeroid syndromes. The present results indicate that the monkey suffers from a kind of progeria that is not necessarily typical to human progeroid syndromes.

Figure 1. Monkey N416 resembled aged monkeys in appearance.

A: Monkey N416 (10 months old) and her mother. Note that deep wrinkles of the skin are seen in monkey N416. B: Monkey N416 at the age of 1 year and 10 months. Cataract was first recognized in one eye when she was 10 months old and, progressed bilaterally within a few months (pointed to by arrows). The deep skin wrinkles become rather reduced as the body grows. C: Three-dimensionally-reconstructed CT image of monkey N416 (2 years and 5 months old). Note that the deep skin wrinkles clearly remain in both the scalp and the postcranial skin. D: Three-dimensionally-reconstructed CT image of an age-matched control. In this monkey, the skin is smooth. Semi-transparent objects are parts of the stereotaxic apparatus.

Figure 2. Fibroblast cells derived from monkey N416 resembled those derived from progeroid patients in cell biological features.

A: Histograms of cell division intervals of fibroblasts derived from monkey N416 and a control monkey (Ctrl) at passage 5. Note that the time of cell division is significantly longer in monkey N416 (28.8±6.6 hr; n = 44) than in the control (20.0±4.6 hr, n = 47). B: Population growth of fibroblast cells derived from a normal aged monkey, a normal infant monkey, and monkey N416 at passage 8. C: Ratio of senescent-associated ß-galactosidase-positive fibroblast cells derived from monkey N416, in comparison with those derived from aged and infant monkeys (**: p<0.01). Photographs are representative images. D: Number of apurinic/apyrimidinic (AP) sites per 100,000 bp in fibroblast cells derived from monkey N416, in comparison with those from aged and infant monkeys and, also, UV-irradiated cells from the infant monkey (*: p<0.05, **: p<0.01).

Figure 3. Monkey N416 resembled progeroid patients in metabolic and dermatological features.

A,B: Levels of blood HbA1c (A) and urinary hyaluronan (B) in monkey N416 and the aged, adult, and child monkey groups. A significant difference between monkey N416 and the adult monkey group or between monkey N416 and the child monkey group is indicated (*: p<0.05, **: p<0.01). C,D: Poikiloderma with superficial telangiectasia of the skin in monkey N416. Atrophy in dermis is observed in C, while slight acanthosis in epidermis and expanded capillary in the superficial region of dermis (arrow) are seen in D (specified by the box in C). Bars, 1 mm in C and 100 µm in D.

Figure 4. Shrinkage of the cerebral cortex and the hippocampus in monkey N416 was revealed with MRI.

A,C,D: Parasagittal images of monkey N416 (1 year and 5 months old), an age-matched control, and an aged monkey (28 years old), respectively. Note that expansion of the cerebral sulci (arrows) in monkey N416 is as large as and expansion of the lateral ventricles (arrowheads) is larger than those in the aged monkey. This is probably ascribed to shrinkage of the cerebral cortex and the hippocampus. B: Coronal image of monkey N416. Seen is prominent expansion of the lateral ventricles (arrowheads).

Figure 5. Conduction velocity of peripheral sensory but not motor nerve was slower in monkey N416.

Measured from the ulnar nerve. A: Sensory conduction velocity (SCV). The SCV in monkey N416 and aged monkeys was slower than that in adult and child monkeys. **: p<0.01, *: p<0.05 (one-way ANOVA and Bonferroni post hoc test). B: Motor conduction velocity (MCV). The MCV in monkey N416 was similar to that in aged, adult, and child monkeys. C: SCV versus MCV in individual monkeys. Ovals indicate 1.5 standard deviation limits. Note that each age group makes a cluster, and that the position for monkey N416 is located within the cluster for the aged monkey group.