Aging and longevity are two multifactorial biological phenomena whose knowledge at molecular level is still limited. We have studied proteasome function in replicative senescence and cell survival (Mol Aspects Med 35, 1-71; Ageing Res Rev 23, 37-55). We have observed reduced levels of proteasome content and activities in senescent cells due to the down-regulation of the catalytic subunits of the 20S complex (J Biol Chem 278, 28026-28037). In support, partial inhibition of proteasomes in young cells by specific inhibitors induces premature senescence which is p53 dependent (Aging Cell 7, 717-732). Stable over-expression of catalytic subunits or POMP resulted in enhanced proteasome assembly and activities and increased cell survival following treatments with various oxidants. Importantly, the developed “proteasome activated” human fibroblasts cell lines exhibit a significant delay of senescence (J Biol Chem 280, 11840-11850; J Biol Chem 284, 30076-30086). Similar proteasome activation in human mesenchymal stem cells not only increases their lifespan, but also enhances stemness mediated by Oct4 (Free Rad Biol Med 103, 226-235). Moreover, additional findings indicate that the recorded proteasome activation is mediated by the transcription factors Nrf2 (J Biol Chem 285, 8171-8184) and FoxO1 (Front Cell Dev Biol 9, 625715). Finally, we provide evidence that proteasome activation is an evolutionary conserved mechanism, as it can delay aging in vivo and, importantly, it also confers deceleration of aggregation-related pathologies, such as Alzheimer’s or Huntington’s diseases (FASEB J 29, 611-622). Given these findings, recent work has identified a set of proteasome activators that decelerate aging and Alzheimer’s disease progression in various in vivo models (Antiox Redox Signal 25, 855-869; Free Rad Biol Med 162, 88–103).
We have also developed biobanks of donors of different ages, including healthy centenarians and long-lived siblings. Using these biobanks we have cloned several novel longevity genes (Biogerontology 5, 401-409) and we have found that healthy centenarians have a functional proteasome (Exp Gerontol 35, 721-728). Moreover, we have identified specific somatic point mutations in mtDNA control region (PLoS One 5, e13395; Aging Cell 13, 101-107) and four chromosomal loci (Aging Cell 12, 184-193) that are linked with healthy aging and longevity. Finally, we determine the rate of aging and the efficacy of anti-aging protocols based mainly on the use of natural compounds by analysing various molecular biomarkers in PBMCs of healthy individuals. To this end we measure the levels of several established biomarkers of aging (telomeres length & telomerase activity, proteasome content and function, NAD levels, global DNA methylation, Clu/ApoJ expression, AGE levels, levels of oxidized proteins) in volunteers every 3-6 months. This work leads to the development of personalized anti-aging protocols and innovative wellness products (Antioxidants 11, 468).
Figure 1: Pathways of cellular ageing
Figure 2: Measurement of ageing and age-related disease biomarkers in human population.
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I.P. Trougakos, A. So, B. Jansen, M.E. Gleave and E.S. Gonos (2004) Silencing expression of the Clusterin/Apolipoprotein J gene in human cancer cells using small interfering RNA induces spontaneous apoptosis, reduced growth ability and cell sensitization to genotoxic and oxidative stress. Cancer Res. 64, 1834-1842.
I.P. Trougakos, M. Lourda, G. Agiostratidou, D. Kletsas and E.S. Gonos (2005) Differential effects of clusterin/Apolipoprotein J on cellular growth and survival. Free Rad. Biol. Med. 38, 436-449.
N. Chondrogianni, C. Tzavelas, A.J. Pemberton, I.P. Nezis, A.J. Rivett and E.S. Gonos (2005) Overexpression of proteasome β5 subunit increases amount of assembled proteasome and confers ameliorated response to oxidative stress and higher survival rates. J. Biol. Chem. 280, 11840-11850.
M. Lourda, I.P. Trougakos and E.S. Gonos (2007) Development of resistance to chemotherapeutic drugs in human osteosarcoma cell lines largely depends on up-regulation of Clusterin/Apolipoprotein J. Int. J. Cancer 120, 611-622.
N. Chondrogianni, I.P. Trougakos, D. Kletsas, Q.M. Chen and E.S. Gonos (2008) Partial proteasome inhibition in human fibroblasts triggers accelerated M1 senescence or M2 crisis depending on the p53 and RB status. Aging Cell 7, 717-732. (cover page)
I.P. Trougakos, M. Lourda, M.H. Antonelou, D. Kletsas, V.G. Gorgoulis, I. Papassideri, Y. Zou, L.H. Margaritis, D.A. Boothman and E.S. Gonos (2009) Intracellular Clusterin inhibits mitochondrial apoptosis by suppressing p53-activating stress signals and stabilizing the cytosolic Ku70-Bax protein complex. Clinical Cancer Res. 15, 48-59. (cover page)
I.P. Trougakos, J.Y. Djeu, E.S. Gonos and D.A. Boothman (2009) Advances and challenges in basic and translational research on Clusterin. Cancer Res. 69, 403-406.
E. Balantinou, I.P. Trougakos, N. Chondrogianni, L.H. Margaritis and E.S. Gonos (2009) Transcriptional and post-translational regulation of clusterin by the two main cellular proteolytic pathways. Free Rad. Biol. Med. 46, 1267-1274.
B. Catalgol, I. Ziaja, N. Breusing, T. Jung, A. Höhn, B. Alpertunga, P. Schroeder, N. Chondrogianni, E.S. Gonos, I. Petropoulos, B. Friguet, L.O. Klotz, J. Krutmann and T. Grune (2009) The proteasome is an integral part of solar ultraviolet A radio-induced gene expression. J. Biol. Chem. 284, 30076-30086.
S. Kapeta, N. Chondrogianni and E.S. Gonos (2010) Nuclear erythroid factor 2 (Nrf2) mediated proteasome activation delays senescence in human fibroblasts. J. Biol. Chem. 285, 8171-8184.
C. Sisoula, V. Trachana, C. Patterson and E.S. Gonos (2011). CHIP-dependent p53 regulation occurs specifically during cellular senescence. Free Rad. Biol. Med. 50, 157-165.
K.S. Leskov, S. Araki, J.P. Lavik, J. Gomez, V. Gama, E.S. Gonos, I.P. Trougakos, S. Matsuyama and D.A. Boothman (2011) Crm1-mediated regulation of nuclear clusterin, an ionizing radiation-stimulated, bax-dependent pro-death factor. J. Biol. Chem. 286, 40083-40090.
D. Jurk, C. Wang, S. Miwa, M. Maddick, V. Korolchuk, A. Tsolou, E.S. Gonos, C. Thrasivoulou, M. Saffrey, K. Cameron and T. von Zglinicki (2012) Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11, 996-1004.
M. Beekman, H. Blanché, M. Perola, A. Hervonen, V. Bezrukov, E. Sikora, F. Flachsbart, L. Christiansen, A.J. De Craen, T.B. Kirkwood, I.M. Rea, M. Poulain, J.M. Robine, S. Valensin, M.A. Stazi, G. Passarino, L. Deiana, E.S. Gonos, L. Paternoster, T.I. Sørensen, Q. Tan, Q. Helmer, E.B. Van den Akker, J. Deelen, F. Martella, H.J. Cordell, K.L. Ayers, J.W. Vaupel, O. Törnwall, T.E. Johnson, S. Schreiber, M. Lathrop, A. Skytthe, R.G. Westendorp, K. Christensen, J. Gampe, A. Nebel, J.J. Houwing-Duistermaat, E.P. Slagboom and C. Franceschi C (2013) Genome-wide linkage analysis for human longevity: Genetics of Healthy Ageing Study. Aging Cell 12, 184-193.
L. Da Silva, M. Godejohann, F.J. Martin, S. Collino, A. Bürkle, M. Moreno-Villanueva, J. Bernhardt, O. Toussaint, B. Grubeck-Loebenstein, E.S. Gonos, E. Sikora, T. Grune, N. Breusing, C. Franceschi, A. Hervonen, M. Spraul and S. Moco (2013) High-Resolution Quantitative Metabolome Analysis of Urine by Automated Flow Injection NMR. Anal. Chem. 85, 5801-5809.
N. Chondrogianni, I. Petropoulos, S. Grimm, K. Georgila, B. Catalgol, B. Friguet, T. Grune and E.S. Gonos (2014) Protein damage, repair and proteolysis. Mol. Aspects Med. 35, 1-71.
N. Raule, F. Sevini, S. Li, A. Barbieri, F. Tallaro, L. Lomartire, D. Vianello, A. Montesanto, J. Moilanen, V. Bezrukov, H. Blanche, A. Hervonen, K. Christensen, L. Deiana, E.S. Gonos, T.B.L. Kirkwood, P. Kristensen, A. Leon, P.G. Pelicci, M. Poulain, I.M. Rea, J. Remacle, J.M. Robine, S. Schreiber, E. Sikora, P.E. Slagboom, L. Spazzafumo, M.A. Stazi, O. Toussaint, J.W. Vaupel , G. Rose, K. Majamaa, M. Perola, T.E. Johnson, L. Bolund, H. Yang, G. Passarino and C. Franceschi (2014) The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific. Aging Cell 13, 101-107.
E. Mocchegiani, L. Costarelli, R. Giacconi, M. Malavolta, A. Basso, F. Piacenza, R. Ostan, E. Cevenini, E.S. Gonos, C. Franceschi and D. Monti (2014) Vitamin E-gene interactions in ageing and inflammatory age-related diseases: implications for treatment. Ageing Res. Rev. 14, 81-101.
N. Chondrogianni, M. Sakellari, M. Lefaki, N. Papaevgeniou and E.S. Gonos (2014) Proteasome activation delays aging in vitro and in vivo. Free Rad. Biol. Med. 71, 303-320.
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N. Chondrogianni, K. Voutetakis, M. Kapetanou, V. Delitsikou, N. Papaevgeniou, M. Sakellari, M. Lefaki, K. Filippopoulou and E.S. Gonos (2015) Proteasome activation: an innovative promising approach for delaying aging and retarding age-related diseases. Ageing Res. Rev. 23, 37-55.
N. Papaevgeniou, M. Sakellari, S. Jha, N. Tavernarakis, C.I. Holmberg, E.S Gonos and N. Chondrogianni (2016) 18α-Glycyrrhetinic acid proteasome activator decelerates aging and Alzheimer’s disease progression in C. elegans and neuronal cultures. Antioxid. Redox Signal. 25, 855-869.
E. Valentini, M. Zampieri, M. Malavolta, M.G. Bacalini, R. Calabrese, T. Guastafierro, A. Reale, C. Franceschi, A. Hervonen, B. Koller, J. Bernhardt, P.E. Slagboom, O. Toussaint, E. Sikora, E.S. Gonos, N. Breusing, T. Grune, E. Jansen, M.E. Dollé, M. Moreno-Villanueva, T. Sindlinger, A. Bürkle, F. Ciccarone and P. Caiafa (2016) Analysis of the machinery and intermediates of the 5hmC-mediated DNA demethylation pathway in aging on samples from the MARK-AGE Study. Aging 8, 1896-1922.
F. Ciccarone, M. Malavolta, R. Calabrese, T. Guastafierro, M.G. Bacalini, A. Reale, J. Bernhard, O. Toussaint, B. Grubeck-Loebenstein, E.S. Gonos, E. Sikora, C. Franceschi, P.E. Slagboom, A. Hervonen, A. Burkle, M. Zampieri and P. Caiafa (2016) Age-dependent expression of DNMT1 and DNMT3B in PBMCs from a large cohort of individuals including centenarian’s offspring. Aging Cell 15, 755–765.
M. Kapetanou, N. Chondrogianni, S. Petrakis, G. Koliakos and E.S. Gonos (2017) Proteasome activation enhances stemness and lifespan of human mesenchymal stem cells. Free Radic. Biol. Med. 103, 226-235.
I. Matis, D.C. Delivoria, B. Mavroidi, N. Papaevgeniou, S. Panoutsou, S. Bellou, K.D. Papavasileiou, Z.I. Linardaki, A.V. Stavropoulou, K. Vekrellis, N. Boukos, F.N. Kolisis, E.S. Gonos, M. Margarity, M.G. Papadopoulos, S. Efthimiopoulos, M. Pelecanou, N. Chondrogianni and G. Skretas (2017) An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding. Nature Biomed. Eng. 1, 838-852.
R. Giacconi, L. Costarelli, F. Piacenza, A. Basso, A. Bürkle, M. Moreno-Villanueva, T. Grune, D. Weber, W. Stuetz, E.S. Gonos, C. Schön, B. Grubeck-Loebenstein, E. Sikora, O. Toussaint, F. Debacq-Chainiaux, C. Franceschi, A. Hervonen, E. Slagboom, F. Ciccarone, M. Zampieri, P. Caiafa, E. Jansen, M.E.T. Dollé, N. Breusing, E. Mocchegiani and M. Malavolta (2018) Zinc-induced Metallothionein in centenarian offspring from a large European population: the MARK-AGE Project. J. Gerontol. 73, 745-753
E.S. Gonos, M. Kapetanou, J. Sereikaite, K. Naparło, M. Grzesik, G. Bartosz and I. Sadowska-Bartosz (2018) Origin and pathophysiology of protein carbonylation, nitration and chlorination, particularly in age-related brain diseases and brain aging. Aging 10, 868-901.
A.L. Cardoso, A. Fernandes, J.A. Aguilar-Pimentel, M.H. de Angelis, J.R. Guedes, M.A. Brito, S. Ortolano, G. Pani, S. Athanasopoulou, E.S. Gonos, M. Schosserer, J. Grillari, P. Peterson, B.G. Tuna, S. Dogan, A. Meyer, R. van Os and A.U. Trendelenburg (2018) Candidates from genes and pathways regulated in aging and age-related diseases. Ageing Res. Rev. 47, 214-277.
I. Pinchuk, D. Weber, B. Kochlik, W. Stuetz, O. Toussaint, F. Debacq-Chainiaux, M.E.T. Dollé, E.H.J.M. Jansen, E.S. Gonos, Ε. Sikora, N. Breusing, D. Gradinaru, T. Sindlinger, M. Moreno-Villanueva, A. Bürkle, T. Grune and D. Lichtenberg (2019). Gender- and age-dependencies of oxidative stress, as detected based on the steady state concentrations of different biomarkers in the MARK-AGE study. Redox Biol. 24, 101204.
R. Giacconi, F. Maggi, L. Macera, P.G. Spezia, M. Pistello, M. Provinciali, F. Piacenza, A. Basso, A. Bürkle, M. Moreno-Villanueva, M.E.T. Dollé, E. Jansen, T. Grune, W. Stuetz, E.S. Gonos, C. Schön, J. Bernhardt, B. Grubeck-Loebenstein, E. Sikora, M. Dudkowska, D. Janiszewska, O. Toussaint, F. Debacq-Chainiaux, C. Franceschi, M. Capri, A. Hervonen, M. Hurme, E. Slagboom, N. Breusing, E. Mocchegiani and M. Malavolta (2020) Prevalence and Loads of Torquetenovirus in the European MARK-AGE Study Population. J. Gerontol. 75, 1838–1845.
A. Mladenovic Djordjevic, N. Loncarevic-Vasiljkovic and E.S. Gonos (2021) Dietary restriction and oxidative stress: friends or enemies? Antioxid. Redox Signal. 34, 421-438.
A. Mladenovic-Djordjevic, M. Kapetanou, N. Loncarevic-Vasiljkovic, S. Todorovic, S. Athanasopoulou, M. Jovic, M. Prvulovic, E. Taoufik, R. Matsas, S. Kanazir and E.S. Gonos (2021) Pharmacological intervention in a transgenic mouse model improves Alzheimer’s-associated pathological phenotype: Involvement of proteasome activation. Free Radic. Biol. Med. 162, 88–103.
M. Kapetanou, T. Nespital, L.S. Tain, A. Pahl, L. Partridge and E.S. Gonos (2021) FoxO1 is a novel regulator of 20S proteasome subunits expression and activity. Front. Cell Dev. Biol. 9, 625715.
F. Piacenza, R. Giacconi, L. Costarelli, A. Basso, A. Bürkle, M. Moreno-Villanueva, M.E.T. Dollé, E. Jansen, T. Grune, D. Weber, W. Stuetz, E.S. Gonos, C. Schön, J. Bernhardt, B. Grubeck-Loebenstein, E. Sikora, O. Toussaint, F. Debacq-Chainiaux, C. Franceschi, M. Capri, A. Hervonen, M. Hurme, E. Slagboom, N. Breusing, E. Mocchegiani and M. Malavolta (2021) Age, sex and BMI influence on copper, zinc and their major serum carrier proteins in a large European population including Nonagenarian Offspring from MARK-AGE study. J Gerontol, 76, 2097-2106.
S. Athanasopoulou, M. Kapetanou, M.G. Magouritsas, N. Mougkolia, P. Taouxidou, M. Papacharalambous, F. Sakellaridis and E.S. Gonos (2022) Antioxidant and antiaging properties of a novel synergistic nutraceutical complex: Readouts from an in cellulo study and an in vivo prospective, randomized trial. Antioxidants 11, 468.