Making mice live longer, then humans

Invariably, everyone gets old. However, as a true testament to human stubbornness, research toward a “cure” for aging has never stopped. Over the past few decades, various approaches have allowed scientists to generate animal models with extended lifespans. In recent years, this trend has moved from lower organisms to mammalian model systems. There are now several rodent models with enhanced longevity. Many of these models are directly relevant to human aging.

A new study has identified a deletion in exon 3 of human growth hormone receptor (GHR) to be prevalent in naturally long-lived men¹. The presence of two copies of this mutation may allow men to live about ten years longer than they otherwise would. This agrees with many findings from rodent models. Transgenic mice that overexpress GH age rapidly, while knockout mice lacking GHR are long-lived^2,3. In humans and mice, IGF1 signaling is also closely linked to longevity via a signaling pathway overlapping that of GH^4,5.

Pathways involved in managing oxidative stress have also been implicated in mammalian aging. Deletion of the proapoptotic gene p66Shc has been shown to significantly extend longevity in mice, and ectopic targeting of catalase to mitochondria in transgenic mice leads to reduction of many age-associated health issues^{6, 7}.

Some other mouse models with increased longevity include knockout of type 5 adenylyl cyclase, which increases median lifespan by 30%, and knockout of the RIIβ isoform of PKA, which extends male mouse longevity and increases age-related health^{8, 9}.

In the coming years, there will likely be even more progress in lifespan extension, perhaps even including direct applications to humans.

References

1. Ben-Avraham D, Govindaraju DR, Budagov T, Fradin D, Durda P, Liu B, Ott S, Gutman D, Sharvit L, Kaplan R, Bougnères P, Reiner A, Shuldiner AR, Cohen P, Barzilai N, Atzmon G. The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature. Sci Adv. 2017 Jun 16;3(6):e1602025.
2. Bartke A. Pleiotropic effects of growth hormone signaling in aging. Trends Endocrinol Metab. 2011 Nov;22(11):437-42.
3. Junnila RK, Duran-Ortiz S, Suer O, Sustarsic EG, Berryman DE, List EO, Kopchick JJ. Disruption of the GH Receptor Gene in Adult Mice Increases Maximal Lifespan in Females. Endocrinology. 2016 Dec;157(12):4502-4513.
4. Milman S, Atzmon G, Huffman DM, Wan J, Crandall JP, Cohen P, Barzilai N. Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell. 2014 Aug;13(4):769-71.
5. Holzenberger M, Dupont J, Ducos B, Leneuve P, Géloën A, Even PC, Cervera P, Le Bouc Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature. 2003 Jan 9;421(6919):182-7.
6. Trinei M, Berniakovich I, Beltrami E, Migliaccio E, Fassina A, Pelicci P, Giorgio M. P66Shc signals to age. Aging (Albany NY). 2009 Jun 5;1(6):503-10.
7. Treuting PM, Linford NJ, Knoblaugh SE, Emond MJ, Morton JF, Martin GM, Rabinovitch PS, Ladiges WC. Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria. J Gerontol A Biol Sci Med Sci. 2008 Aug;63(8):813-22.
8. Yan L, Vatner DE, O'Connor JP, Ivessa A, Ge H, Chen W, Hirotani S, Ishikawa Y, Sadoshima J, Vatner SF. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell. 2007 Jul 27;130(2):247-58.
9. Enns LC, Morton JF, Treuting PR, Emond MJ, Wolf NS, Dai DF, McKnight GS, Rabinovitch PS, Ladiges WC. Disruption of protein kinase A in mice enhances healthy aging. PLoS One. 2009 Jun 18;4(6):e5963.