Aging corresponds to the set of physiological processes that modify the structure and functions of the organism according to the time and stresses undergone. Intrinsic aging due to genetic factors and biochemical modifications that take place during states of fatigue and stress and hormonal changes such as pregnancy, etc., may be distinguished from extrinsic aging due to environmental factors to which the organism is subjected throughout its life, such as pollution, sunlight, disease, lifestyle, etc. Aging is a slow and progressive process that affects all cells and organs. Thus this applies to the skin, which constitutes a barrier between the external environment and the inner medium and protects the organism against external stresses. During aging, the appearance of the skin changes and thus wrinkles and fine lines, hyper- or hypopigmentation spots, dryness and even dehydration of the skin, thinning of the epidermis, elastosis, etc., may appear.
Intrinsic aging is closely linked to the repeated divisions of cells. Thus, in human somatic cells, telomeres shorten the rhythm of cellular division, until dysfunctional telomeres appear that induce senescence or apoptosis, depending on the cellular type. This phenomenon constitutes the biological clock that explains the fact that human somatic cells are programmed for a limited number of divisions.
Cellular senescence phenomena are accelerated by oxidative damage, particularly in areas of the body where the skin is exposed to the sun; Photo aging is then superimposed on intrinsic aging. Oxidative damage is promoted by various agents, both endogenous (metabolism, inflammation, redox cycles) and exogenic, such as UV radiation and ionizing radiation, tobacco abuse and various molecules supplied by the diet (toxic metals, alcohol). Damage caused by oxidative stress also reaches the DNA and lipids and proteins. At the DNA level, oxidative stress causes many structural modifications (mutations, cleavage, covalent protein cross-links). Oxidized bases, such as 8-oxo-guanine, increase with age and may reach up to 10,000 bases per day and per cell.
To combat aging, it is therefore of interest to identify novel compounds capable of both combating localized damage caused to the DNA by oxidative stress and slowing down cellular senescence by promoting telomere stability.
Such being the case, the inventors have recently identified an interesting molecular target capable of fulfilling these various functions.
SIRT proteins are nuclear or mitochondrial proteins, bearing a NAD+dependent deacetylase function and belonging to the sirtuin family. The deacetylase or mono-ADP-ribosyltransferase activity of sirtuins enables them to modulate the acetylation level of some histones, which suggests their involvement, particularly with 1, 2 and 3 sirtuins, in the regulation of epigenetic phenomena.
The human sirtuin family comprises 7 proteins, very conserved throughout evolution, named SIRT1 to SIRT7.
SIRT6 is a nuclear sirtuin specifically associated with telomere chromatin and plays a role in the maintenance and stabilization of telomeric structures (Michishita et al. Nature. 2008 Mar. 27; 452(7186):492-6). Thus, in the mouse invalidated for the SIRT6 gene, premature aging and a short lifespan are observed, as well as an increase in the replicative senescence of keratinocytes (Kawahara T L et al. Cell. 2009 Jan. 9; 136(1):62-74).
Telomeres are structures that cover the ends of chromosomes and protect chromosomes against enzymatic degradation, recombination and interchromosomal fusion. In humans, these structures are constituted of a DNA sequence repeated thousands of times, associated with specific proteins, such as TRF1 and TRF2. Recent studies have shown that the TRF2 expression declines during cell aging (Amoyel et al., J. Invest. Dermatol. April 2009; 129 (Supplement 1s), s70).
On the other hand, SIRT6 plays an important role in DNA repair by bases excision, a DNA repair mechanism utilized by the cell when the DNA has been damaged by oxidants. These discoveries suggest that SIRT6 is necessary for regulating genome integrity and aging phenomena and may be directly involved in the increase of cellular longevity (Mostoslaysky et al., Cell. 2006 Jan. 27; 124(2):315-29).
It is known that the utilization of SIRT1 protein activating peptides (FR 2883751, FR 2883752, FR 2883753, FR 2883754), enables cosmetic or pharmaceutical compositions useful for protecting the skin and combating aging to be prepared, or else that certain SIRT7 inducer pharmaceutical compounds are useful for treating age-related diseases (EP 1955715). However, to date, no peptide compound capable of activating the SIRT6 protein in skin cells has been described, while the need for this type of skin care exists.
USPTO Backgrounds
USPTO Backgrounds