NeoSENS

In 2002 Aubrey de Grey coined the term Strategies for Engineered Negligible Senescence (SENS), an approach to dealing with aging that seeks to attain maximum clinical results with minimal knowledge on the complexities of the underlying molecular mechanisms. Consequently SENS is not as concerned about the causes of subtleties such as perturbed gene expression as it is about addressing their physiological consequences. Using this approach, he proposed seven methods of addressing what he determined were the most prominent outcomes of aging. Whilst he has was successful in capturing certain segments of the public imagination and aroused great curiosity in the press as to the proximity of a solution to aging using his proposed methods, the mainstream scientific community were less than captivated due to the speculative nature of the technologies that SENS interventions rely on (in some cases they have yet to be invented).

In 2004 Jay D Fox suggested an alternative to one of the SENS proposals that seeks to deal with the problem of chromosomal damage and cancer (Whole-body Interdiction of Lengthening Telomeres (WILT)) based upon an analysis of stem cell turnover in the gut epithelium. Harold Brenner then coined the term "neoSENS" to describe a set of theoretical proposals in the spirit of SENS yet in contrast to it by relying on existing technologies instead of futuristic ones. The core imperative of the neoSENS hypotheses was to establish experimental protocols which could be implemented using available technology and consequently could deliver anti-aging inteventions faster than SENS proposed to.

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Aging & DNA Damage

It was Kirkwood^[1] who first proposed that the drive to increase biological process efficiency placed a limit on the resources that could be allocated to the maintenance of information in cells. Consequently it would not be efficient to maintain 100% repair in cells. DNA is expected, and has been observed, to accumulate damage.

Nuclear versus Mitochondrial DNA damage

  Whilst there is a broad agreement within the scientific community that DNA damage contributes to aging, there has been great resistance by SENS advocates to accept that nuclear DNA (nDNA) damage, as distinct from mitochondrial DNA (mtDNA) damage, contributes to much more than the cancer phenotype. This position maintains that nDNA mutations threaten the organism only in respect to cancer incidence and that when mutations are sufficient to cause cellular dysfunction that it is so rare an event that it should be considered negligible. In contrast, it is the view of neoSENS proponents that nDNA damage is central to the process of aging and that cancer is but one of many consequences.

Nuclear DNA encodes 99.999% of the genes in the mammalian cell. Damage can interfere with transcription related processes which in turn can result in genes important to cell and tissue function being switched off and in genes that normally are silenced to be switched on (ie oncogene activation). We know that providing double strand breaks do not occur a cell can survive a great deal of damage to its DNA.^[2] Even if such damage is not properly corrected^[3] resulting in possible transcription errors and alteration to binding sites. With the enormous diversity of genes existent in the nucleus it is possible that compensatory mechanisms could be activated when one gene whose function could be to produce a ligand, transcription factor or other network component becomes silenced. Such transformation would result in more subtle and ambiguous phenotypic effects. Ultimately, however, the accumulation of such events would result in increasing inefficiencies. In parallel, one must consider the role that nDNA damage may have on mtDNA function and inevitably damage considering that the vast majority of mitochondrial genes are encoded in the nucleus. As an example nuclear encoded mitochondrial antioxidant protein superoxide dismutase (SOD) is significantly lowered in aged rats which would in turn destabilize mitochondria due to increased ROS.^[4] If lowered SOD levels are due to global reduction in protein synthesis due to DNA damage then mtDNA damage becomes a function of nDNA damage. SOD is of course one of many enzymes involved in mitochondria that could be down-regulated due to nDNA damage. See also DNA Repair.

Comparing SENS and neoSENS

The way that neoSENS differs with SENS is better illustrated by comparing the approaches to mitochondrial DNA damage:

SENS: allotopic expression of mitochondrial genome

Supporting research: NEGATIVE Only a subset of mitochondrial genes can be replaced allotopically. Analyses of the hydrophobic patterns of different polypeptides suggest that hydrophobicity of the N-terminal segment is the main determinant for the importability of peptides into mammalian mitochondria.^[5]

neoSENS: increase mitochondrial DNA repair by directing the overexpression of DNA repair enzymes in mitochondria

Supporting research: POSITIVE Functional studies revealed that cells containing recombinant OGG1 were more proficient at repairing oxidative damage in their mtDNA, and this increased repair led to increased cellular survival following oxidative stress.^[6]

References