Naked Mole Rats (NMR), native to parts of East Africa, are extremely long lived rodents, living up to 8x's longer than comparably sized mice. This is equivalent to a humans living to be 800 years! Better yet, the NMR maintain their vitality and health to almost the end of their lives, including brains which are resistant to degeneration. So, what is behind such extreme longevity?
The key is enhanced cellular protein homeostasis. (1-3) Key regulators of the aging process is the ability to maintain cellular quality including the removal of defective, damaged and toxic proteins. In the cell, proteasomes, the cellular machinery which removes damaged protein in conjunction with lysosomal autophagy are involved in the removal of damaged protein and cellular components. NMR maintain a very high level of protein homeostasis by enhanced activity of proteasomes and maintaining high active levels of autophagy.
Increased proteasome and autophagy activity extends lifespans in animal experiments. However, dysfunction of protein homeostasis increases with age, and leads to cellular accumulation of damaged protein, and the onset of disease and aging. In Alzheimer's Disease, for example, damaged proteins (amyloid and tau proteins) begin to aggregate, and eventually kill the surrounding neurons. Normal protein homeostasis is disrupted in Alzheimer's Disease, and most notably impairment of autophagy.(4)
PROTEIN HOMEOSTASIS is essential for extreme longevity. The two primary molecular mechanisms for maintaining health cell quality control and protein are: Proteasomes and Autophagy. "Aging is considered to be the loss of physiological integrity accompanied by a cumulative dysfunction in securing cellular homeostasis, resulting in the accumulation of damage and a progressive decline of cellular function over time." (7)
FOXO Nrf2 (transcription factors) AND PROTEIN HOMEOSTASIS:
(1) Triplett JC, et al. Age-related changes in the proteostasis network in the brain of the nakedmole-rat. Implications promoting healthy longevity. BiochimBiophys Acta. 2015 Oct.
(2) Triplett JC, et al. Metabolic clues to salubrious longevity in the brain of the longest-lived rodent: the naked mole-rat. J Neurochem. 2015 Aug.
(3) Pride H, et al. Long-lived species have improved proteostasis compared to phylogenetically-related shorter lived species. Biochem Biophys Res. Commun. 2015 Feb.
(4) Chondrogianni N, et al. 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans. FASEB J. 2015 Feb
(5) Chondrogianni N, et al. Enhanced proteasome degradation extends Caenorhabditis elegans lifespan and alleviates aggregation-related pathologies. Free Radic Biol Med. 2014 Oct.
(6) Salminen A, et al. Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome. Prog. Neurobiol. 2013 Jul-Aug;
(7) Grimmel M, et al. WIPI-Mediated Autophagy and Longevity. Cells. 2015 May.
(8) Liu Y, et al. Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington's disease. J Neurochem 2014 May
(9) Chapple SJ, et al. Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging. Int J Biochem Cell Biol. 2012 Aug
(10) Murshid A, et al. Stress proteins in aging and life span. Int J Hyperthermia. 2013 Aug.
(11) Calderwood SK, et al. The shock of aging: molecular chaperones and the heat shock response in longevity and aging--a mini-review. Gerontology. 2009.
(12) Webb AE, et al. FOXO transcription factors: key regulators of cellular quality control. Trends Biochem Sci. 2014 Apr.
(13) Pickering AM, et al. Nrf2-dependent induction of proteasome and Pa28αβ regulator are required for adaptation to oxidative stress. J Biol Chem. 2012 Mar.
(14) Gan N, et al. Sulforaphane activates heat shock response and enhances proteasome activity through up-regulation of Hsp27. J Biol Chem. 2010 Nov.
(15) Testa G, et al. Calorie restriction and dietary restriction mimetics: a strategy for improving healthy aging and longevity. Curr. Pharm Des. 2014
(16) Petrovski G, et al. Does autophagy take a front seat in lifespan extension? J Cell Mol Med. 2010 Nov
(17) Alavez S, et al. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature. 2011 Apr.